Salinan Terjemahan Food Toksikologi-Dikompresi-Halaman-1213-1253

BAB 30
MAKANAN
TOKSIKOLOGI
Frank N. Kotsonis dan George A. Burdock

Pentingnya Pelabelan
TOLERANSI SETTING UNTUK SUBSTANCES DALAM

PENGANTAR MAKANAN TOKSIKOLOGI MAKANAN
Keunikan Makanan Toksikologi Alam dan Residu Pestisida
Kompleksitas Makanan Pentingnya Obat-obatan yang Digunakan di dalam Makanan
Pencernaan pertumbuhan, Penyimpanan,
KEAMANAN STANDAR MAKANAN, atau Pengolahan Logam Berat diklorinasi
BAHAN MAKANAN, dan kontaminan Organics nitrosamin, nitrosamida dan N-
Nitroso
The FD & C Act Menyediakan untuk Pendekatan
Zat Makanan-ditanggung Cetakan dan Mycotoxins
Praktis
Solanin dan Chaconine Ethyl karbamat Trans Fatty Acids
The Penerapan Pengalaman: Umumnya Diakui Furan Dinoflagellata Keracunan (paralitik Kerang
sebagai Aman (GRAS) Penggunaan Toleransi Keracunan
Makanan dan Aditif Warna Metode yang atau PSP; Saxitoxin)
Digunakan untuk Mengevaluasi Keamanan Menambahkan Zat —
Makanan, Fluorida
Bahan, danPencemar Paparan: Diperkirakan
Pengambilan Asupan Harian Tingkat Permasalahan BAHAN UNTUK TOLERANSI YANG MUNGKIN TIDAK
(CL) dan Diperlukan DITET
Pengujian Keselamatan Penentuan Aditif Makanan APKAN
Tidak Langsung Persyaratan Keselamatan untuk Zat Racun dalam Ikan, Kerang, dan
GRAS Pentingnya Konsep GRAS Penyu
Pabrik Transgenik (dan Varietas Tanaman Baru) Keracunan Keracunan Neurotoxic (NSP) Keracunan
Metode Kebijakan untuk Menetapkan Kondisi Kerang Amnesik (Asam Domoik) Keracunan Cytacin
Penggunaan yang Aman untuk Poisoning Poisoning Poison Poisoning Poisoning
Makanan Baru Nanoteknologi Persyaratan (Pyropheophorbide) Sea Urchin Keracunan Sea Turtle
Keselamatan untuk Suplemen Diet Penilaian Keracunan Penyakit (Chelonitoxin) Haff mikrobiologi
Karsinogenisitas Agen-preformed bakteri Racun
Karsinogenisitas sebagai Masalah Clostridium Botulinum, C. butyricum dan C. Baratti
Khusus Biologis vs. Statistik Clostridium perfringens Bacillus cereus Staphylococcus
Signifikansi Karsinogenik Con aureus Escherichia coli Zat Bovine Spongiform
taminants Encephalopathy Diproduksi oleh Memasak
heterosiklik Amine Acrylamide
KESELAMATAN
Miscellaneous Kontaminan dalam
MAKANAN
Makanan
Efek Samping terhadap Makanan atau Bahan
KESIMPULAN
Makanan Alergi Makanan
Keracunan Makanan
(Keracunan) Makanan Reaksi
Anafilaktoid Makanan
Makanan Interaksi Obat- PENGANTAR TOXICOLOGY MAKANAN
obatan Metabolik Makanan
Diet khas Barat mengandung ratusan ribu zat yang secara alami menggigit kedua secara berurutan. Sementara zat yang terkandung
terdapat dalam makanan dan banyak lagi yang terbentuk secara in situ dalam makanan bisa berupa nutrisi dan / atau memuaskan, mereka
ketika makanan dimasak atau disiapkan. Banyak dari zat-zat ini mungkin tidak selalu "aman" dalam pun jumlah berapaatau untuk apa
mempengaruhi kualitas nutrisi dan estetika makanan termasuk pun yang penggunaandimaksudkan. Undang-undang Makanan, Obat-
penampilan obatan, dan Kosmetik Federal (FD&C) memberi pemerintah federal
dan sifat organoleptik (yaitu, memberi rasa, tekstur, atau aroma) yang
menentukan apakah kita akan mencoba makanan atau tidak, atau 1191
Hak Cipta © 2008 oleh The McGraw-Hill Companies, Inc. Klik di sini untuk ketentuan penggunaan.
1192 UNIT 7 APLIKASI TOXICOLOGY
Seperti halnya makanan, pendekatan yang praktis dan bisa
diterapkan harus ditemukan untuk kontaminan bahan
tambahan, karena semua zat mengandung segudang
berwenang untuk memastikan bahwa semua makanan yang kontaminan pada jejak atau bahkan jumlah yang tidak
terlibat dalam perdagangan antar negara aman. Kongres, dalam terdeteksi dengan teknologi saat ini. Dalam hal ini, pendekatan
menulis Undang-Undang (dan amandemen selanjutnya), ini melibatkan penetapan batas spesifikasi pada kontaminan
memahami bahwa keselamatan tidak dapat dibuktikan secara yang dimaksudkan untuk mengeluarkan kemungkinan bahwa
absolut dan diindikasikan sebagai pengganti bahwa standar kadar yang ada dalam aditif dapat mengubah makanan yang
keamanan untuk zat-zat yang ditambahkan ke makanan tidak ditambahkan zat tersebut, tidak aman. Harus ditekankan bahwa
lebih dari kepastian yang wajar untuk tidak membahayakan. spesifikasi dapat melayani tujuannya untuk memastikan
Seperti yang akan ditunjukkan dalam bagian lain bab ini, kemurnian yang sesuai hanya jika proses manufaktur yang
bahasa Undang-Undang FD&C secara efektif menyediakan digunakan cukup terkontrol untuk memastikan konsistensi
pendekatan praktis dan bisa diterapkan untuk penilaian dalam kualitas dan kemurnian produk. Filosofi di mana
keamanan makanan, bahan makanan, dan kontaminan spesifikasi ditetapkan untuk zat yang ditambahkan ke makanan
makanan. Karena makanan sangat kompleks, kerangka hukum mewujudkan keyakinan bahwa tidak semua risiko layak untuk
yang disediakan oleh Kongres untuk pengaturan makanan dan diperhatikan dan dikendalikan oleh peraturan (yaitu, konsep de
zat dalam makanan dibuat sederhana sehingga dapat bekerja. minimis).1 Tersirat dalam filosofi ini adalah konsep pemersatu
Elemen dasar dari kerangka kerja ini adalah bahwa makanan, penting ambang batasdalam penilaian keamanan pangan
yang didefinisikan sebagai barang atau komponen barang yang (Flamm et al., 1994, 2002).
digunakan untuk makanan atau minuman untuk manusia atau
Makanan, sebagaimana dinyatakan sebelumnya, mengandung
hewan, memiliki anggapan keselamatan [Bagian 201 (f) dan
ratusan ribu zat, yang sebagian besar belum dikarakterisasi atau
402 (a) (1) UU FD&C]. Ini berarti bahwa steak atau kentang
diuji sepenuhnya. Anggapan bahwa makanan itu aman
dianggap aman kecuali jika mengandung sejumlah zat beracun
didasarkan pada sejarah penggunaan umum dan bahwa
atau merusak dalam jumlah tertentu, yang terbukti membuatnya
konsumsi makanan tertentu berakar dalam pada kondisi. Ketika
berbahaya bagi kesehatan. Intinya, anggapan keselamatan ini
ketidakpastian tentang risiko zat yang ditambahkan adalah
lahir dari keharusan. Jika ratusan ribu zat yang ada dalam
makanan secara alami tunduk pada batasan dan pembatasan
yang sama yang berlaku untuk zat tambahan, hampir semua
1 de minimis non curat praetor atau de minimis non curat lex,
makanan akan dicurigai dan kekurangan makanan dapat dengan
mudah terjadi. Untuk menghindari krisis semacam itu, Kongres dalam arti bahwa hukum tidak tertarik pada hal-hal sepele. Dalam hal
mengembangkan standar keamanan yang tidak akan memaksa ini, risiko sangat kecil sehingga tidak layak dikhawatirkan.
otoritas pengaturan untuk melarang makanan tradisional yang kecil dibandingkan dengan ketidakpastian menghadiri makanan
umum. Dalam kasus di mana zat tidak secara alami ada dalam itu sendiri, standar "kepastian yang masuk akal tidak ada
makanan tetapi merupakan kontaminan atau bahan tambahan, salahnya" untuk zat yang ditambahkan telah terpenuhi. Jadi,
standar keamanannya sangat berbeda. Standar ini menetapkan untuk zat yang menyerupai makanan, anggapannya adalah
makanan yang akan dicemari jika mengandung zat beracun atau bahwa zat itu menyerupai makanan, dicerna dan dimetabolisme
merusak yang dapat menyebabkannya berbahaya. sebagai makanan, dan akibatnya menimbulkan lebih sedikit
Jadi, untuk zat tambahan dan kontaminan, Kongres mengakui pertanyaan terkait toksikologi dan keamanan daripada zat yang
bahwa zat-zat ini tidak serumit makanan dan karenanya harus tidak menyerupai makanan. Selain itu, ketika zat-zat non-
memenuhi standar keamanan yang lebih tinggi. Namun, karena makanan ditambahkan hanya dalam jumlah yang sangat sedikit
baik undang-undang maupun peraturan Administrasi Makanan atau sedikit, tingkat rendah dari paparan paparan dalam
dan Obat-obatan (FDA) atau Departemen Pertanian AS menunjukkan bahwa kondisi penggunaan zat-zat ini
(USDA) tidak secara eksplisit mendefinisikan istilah dimaksudkan aman. Namun, generalisasi yang luas ini tidak
"keamanan" untuk zat-zat yang ditambahkan ke dalam cukup untuk mengecualikan bahan makanan ini dari
makanan, para ilmuwan dan rekanan hukum dan peraturan persyaratan evaluasi keselamatan menyeluruh.
mereka telah menyusun definisi operasional untuk keamanan Selama dekade terakhir, ada peningkatan minat dari pihak
zat tersebut. konsumen tentang sifat makanan yang meningkatkan kesehatan
dan komponen yang dikandungnya. Zat seperti pitosterol dari hampir semua budaya, dan karena sebagian besar makanan
minyak nabati dan isoflavon dari kedelai telah diisolasi dan tidak dapat diproduksi secara komersial di lingkungan yang
ditambahkan ke makanan lain pada level tinggi untuk dapat ditentukan di bawah kontrol kualitas yang ketat, makanan
memberikan kemampuan menurunkan kolesterol. Produk- pada umumnya tidak dapat memenuhi standar ketat dari
produk tersebut telah menimbulkan pertanyaan peraturan identitas kimia, kemurnian, dan praktik manufaktur yang baik
tentang apakah zat-zat ini berfungsi sebagai obat, dan harus yang dipenuhi oleh sebagian besar produk konsumen. Fakta
diatur seperti itu, atau apakah zat-zat tersebut harus dipandang bahwa makanan dipanen dari tanah, laut, perairan pedalaman,
sebagai zat baru dan diizinkan dalam makanan, seperti halnya atau berasal dari hewan darat, yang tunduk pada kekuatan alam
vitamin C dan zat besi. Baru-baru ini, para ahli dalam ilmu gizi yang tidak terduga, membuat kekonstanan makanan mentah
menyimpulkan bahwa konsep nutrisi harus diperluas untuk tidak dapat diandalkan. Pengalaman telah mendukung
memasukkan semakin banyak konstituen makanan yang keamanan makanan yang biasa dikonsumsi, dan praktik
diinginkan yang menghasilkan manfaat kesehatan yang dapat pertanian yang baik (GAP) di mana makanan diproduksi
diukur terkait dengan pencegahan penyakit (Sansalone, 1999). mengamanatkan perlunya kontrol kualitas (yaitu, Good
Isolasi dan identifikasi dengan komponen makanan baru ini Manufacuring Practice, cGMP) saat ini. Namun demikian, jelas
akan memerlukan evaluasi keselamatan menyeluruh pada bahwa makanan dipegang dengan standar yang berbeda sebagai
tingkat asupan yang dimaksudkan dan untuk populasi pada masalah praktis yang ditentukan oleh kebutuhan.
umumnya (Mackey dan Kotsonis, 2002). Makanan juga memperoleh keunikan dari nutrisi esensialnya,
Akhirnya, harus diakui bahwa di sebagian besar dunia, yang, seperti Vitamin A, mungkin beracun pada tingkat hanya
kontaminasi mikrobiologis makanan sejauh ini merupakan 10 kali lipat di atas yang dibutuhkan untuk mencegah
risiko terbesar yang ditanggung makanan yang dihadapi kekurangan. Evaluasi bahan makanan sering harus
konsumen. Dengan demikian, sementara kewaspadaan dalam mengandalkan alasan yang unik untuk ilmu makanan dalam arti
memastikan keamanan zat yang ditambahkan ke makanan di bahwa zat-zat tersebut mungkin merupakan konstituen
bawah kondisi penggunaan yang dimaksudkan adalah tepat, makanan yang normal atau konstituen makanan yang
kita seharusnya tidak mengabaikan perhatian utama keamanan dimodifikasi sebagai lawan jenis-jenis zat yang biasanya
pangan. ditangani dalam bidang pekerjaan, lingkungan, dan toksikologi
medis. Menilai keamanan zat-zat tersebut, yang ditambahkan
ke makanan untuk efek teknisnya, sering berfokus pada
Keunikan Toksikologi Makanan pencernaan dan metabolisme yang terjadi di saluran pencernaan
(GI). Alasan untuk fokus ini adalah bahwa dalam banyak kasus
Sifat makanan bertanggung jawab atas keunikan racun dicerna
makanan. Makanan menempati posisi yang sangat penting di
BAB 30 30 TOKSIKOLOGI MAKANAN
terdiri dari item nilai kalori dan noncaloric; yaitu, karbohidrat
memasok 47% dari asupan kalori, suplai lemak 37%, dan protein
memasok 16% (ketiganya akan dianggap "makronutrien"), sedangkan
Tabel 30-1 Makanan sebagai mineral dan vitamin, "mikronutrien," jelas tidak memiliki kalori nilai
Campuran Kompleks tetapi tidak kalah penting untuk kehidupan.
Zat non-nutrisi sering dicirikan dalam literatur populer
Nutrisi NON-NutrisiBahan-
sebagai yang dikontribusikan oleh pemrosesan makanan, tetapi alam
Karbohidratbahan alami Protein aditif makanan Lipid menyediakan sebagian besar konstituen non-nutrisi. Misalnya, dalam
kontaminan Mineral Produk pengolahan makanan Vitamin Tabel 30-2 orang dapat melihat bahwa bahkan di antara makanan
“alami” (atau minimal diproses), ada jauh lebih banyak non-nutrisi
SUMBER: Smith RL: Apakah daging satu orang menjadi racun bagi orang lain? daripada konstituen gizi. Banyak dari zat-zat non-nutrisi ini sangat
Transaksi dari Medical Society of London 11 November 1991, hlm. 6. Dengan izin penting untuk pertumbuhan dan kelangsungan hidup tanaman,
dari Medical Society of London.
termasuk hormon dan pestisida alami (diperkirakan sekitar 10.000 oleh
Gold et al. (1992)). Beberapa zat ini mungkin antinutrien (misalnya,
substansi tidak diserap melalui saluran GI; hanya produk
lektin, saponin, trypsin, dan / atau inhibitor chymotrypsin dalam
pencernaannya yang diserap, dan produk ini mungkin identik dengan
kacang kedelai, fitat yang dapat mengikat mineral (hadir dalam
yang berasal dari makanan alami.
kedelai) dan anti-tiamin pada ikan dan tanaman) atau bahkan racun
(misalnya , tomat, sitin) kepada manusia. Suatu gagasan tentang
Alam dan Kompleksitas sejumlah besar zat yang ada dalam makanan diberikan dalam serizat
Makanan Basis Data Senyawadalam Makanan Volatil(BACIS, 1999), di mana
sekitar 5500mudah menguap dicatat terjadi dalam satu atau lebih dari
Makanan adalah campuran nutrisi dan non-nutrisi yang sangat 246 makanan yang berbeda. Namun, ini hanya puncak gunung es,
kompleks baik dikonsumsi dalam bentuk “alami” (tidak diproses) atau karena jumlah bahan kimia alami yang tidak dikenal dalam makanan
sebagai makanan siap saji yang sangat diproses seperti “Makanan Siap jauh melebihi jumlah yang telah diidentifikasi (Miller, 1991).
Makan” ”(MRE) (Tabel 30-1). Di antara substansi "nutrisi", diet Barat Zat non-nutrisi juga ditambahkan sebagai hasil dari proses,
dan pada kenyataannya, 21 CFR 170,3 (o) mendaftar 32 kategori zat hanya kedua setelah hati, dengan reaksi fase (tipe) I dan fase (tipe) II
tambahan langsung, di mana terdapat sekitar 3000 zat individu. Kira- yang lengkap. Sistem monooksigenase enterik analog dengan hati,
kira 2000 di antaranya adalah bahan-bahan perasa, yang sebagian besar karena kedua sistem terletak di retikulum endoplasma sel,
sudah ada secara alami dalam makanan dan tidak bergizi (Burdock,
membutuhkan NADPH dan O2 untuk aktivitas maksimum,
2002). Dari 2000 bahan penyedap yang dapat ditambahkan ke dalam
makanan, kira-kira sepertiga digunakan pada konsentrasi di bawah 10 dihambat oleh banyak zat yang sama, dan secara kualitatif serupa
ppm (Hall dan Oser, 1968), tentang konsentrasi yang sama seperti yang
dalam responnya terhadap induksi enzim (Hassing et al., 1989).
ditemukan secara alami.
Induksi dan penghambatan metabolisme xenobiotik dan efek pada
transporter P-glikoprotein dibahas di bagian lain (lihat bagian interaksi
Pentingnya Saluran Gastrointestinal Makanan-obat).
Konstituen makanan dan ingesta lainnya (misalnya, obat-
Sangat penting untuk menghargai kenyataan bahwa usus adalah organ
obatan, kontaminan, polutan inhalasi yang dilarutkan dalam air liur dan
yang besar, kompleks, dan dinamis dengan beberapa lapisan
tertelan) adalah banyak heterogen secara fisikokimia, dan karena usus
organisasi dan
telah berevolusi menjadi membran yang relatif tidak tembus cahaya,
Tabel 30-2 Zat-Zat Non Gizi dalam
mekanisme penyerapan telah berkembang yang memungkinkan zat
MakananJUMLAHYANG DIIDENTIFIKASI untuk mendapatkan akses ke tubuh dari lumen usus. Empat mekanisme
MAKANANMAKANAN NON-NUTRIEN BAHAN KIMIA utama untuk penyerapan adalah difusi pasif atau sederhana, transpor
aktif, difusi difasilitasi, dan pinositosis. Masing-masing mekanisme ini
Keju Cheddar 160 Jus jeruk 250 secara karakteristik memindahkan sekelompok konstituen yang
Pisang 325 Tomat 350 Anggur 475 ditentukan dari lumen ke dalam tubuh (Tabel 30-3). Seperti dicatat
Kopi 625 Daging sapi (dimasak) 625 dalam tabel, xenobiotik dan zat lain dapat bersaing untuk masuk ke
dalam tubuh.
SUMBER: Smith RL: Apakah daging satu orang menjadi racun bagi orang lain? Membantu penyerapan ini adalah kaya vaskularisasi usus,
Trans Medl Soc Lond 11 November, 6, 1991. Dengan izin dari Medical Society of
London.
dengan laju aliran darah normal di vena portal sekitar 1,2 L / jam / kg.
Namun, setelah makan, ada peningkatan 30% dalam aliran darah
melalui area splanknik (Concon, 1988). Maka kemudian, bahwa zat,
yang mempengaruhi aliran darah, juga cenderung mempengaruhi
permukaan serap yang luas yang diperkirakan sekitar 200 hingga 4.500 penyerapan senyawa; contohnya adalah alkohol, yang cenderung
m2 (Concon, 1988). Waktu transit GI memberikan paparan ingesta meningkatkan aliran darah ke lambung dan dengan demikian
yang memadai terhadap berbagai kondisi lingkungan (yaitu, pH meningkatkan penyerapannya sendiri. Beberapa rangsangan cenderung
variabel), asam pencernaan dan enzim (trypsin, chymotrypsin, dll., mengurangi aliran ke daerah ini, dengan kemungkinan pengecualian
Dari pankreas dan karbohidrat, lipase, dan protease dari enterosit), aktivitas otot yang berenergi dan syok hipovolemik.
agen saponifikasi (dalam empedu), dan flora bakteri mewah yang Sirkulasi getah bening penting dalam transfer lemak, molekul
menyediakan repertoar kemampuan metabolisme yang tidak dimiliki besar (seperti botulinum toxin), benzo [a] pyrene, 3-
oleh inang (misalnya, fermentasi gula “tidak tercerna” seperti xylitol methylcholanthrene, dan cis-dimethylaminostilbene (Chhabra and
dan sorbitol) (Drasar dan Hill, 1974). Enterosit (epitel usus) memiliki
kapasitas yang luas untuk metabolisme xenobiotik yang mungkin
1194 UNIT 7 APLIKASI OF TOXICOLOGY
Tabel 30-3 Sistem Pengangkutan Enteric Constituents
SISTEM KONSTITUEN ENTERI
Gula difusi pasif (misalnya, fruktosa, manosa, dan
xilosa, yang juga dapat diangkut dengan difusi yang difasilitasi), senyawa yang larut dalam lemak, air Difusi terfasilitasi D-xilosa, 6-deoksi-1,5-anhidro-D
glutamat, asam aspartat, asam lemak rantai pendek, xenobiotik dengan gugus karboksi, sulfat, ester glukuronida, timbal, kadmium, seng Kation transpor aktif,
nukleosida (pirimidin, urasil, dan timin, yang dapat berada dalam persaingan dengan 5-fluorouracil dan 5-bromouracil), kobalt, mangan (yang bersaing untu
besi) pinositosis panjang rantai lipid, vitamin B
pewarna azo, antibodi ibu, toksin botulinum, hemagglu tinins, phalloidins, E. coli endotoxins, partikel virus
Eastin, 1984). Limfatik memiliki laju aliran sekitar 1-2 mL / jam / kg pada manusia, dan beberapa faktor diketahui mempengaruhi alirannya, kecuali tripalmitin
menggandakan aliran dan karenanya menggandakan penyerapan. pasam-aminosalicylic dan tetrasiklin (Chhabra dan Eastin, 1984). Faktor lain yang memberi
getah bening adalah fakta bahwa getah bening bermuara melalui saluran rongga dada ke titik persimpangan dari vena jugularis dan subklavia kiri internal, me
"first-pass" oleh hati, tidak seperti zat yang diangkut oleh darah.
Banyak bahan makanan yang dimodifikasi protein, karbohidrat, lemak, atau komponen zat-zat tersebut. Dengan demikian, memahami perubahan zat ini
pencernaan,mungkin mereka
Table30-4 Faktor yang Mempengaruhi Penyerapan usus dan Tingkat Penyerapan
FACTOR CONTOH
sukumengosongkanLambung Peningkatan kadar lemak lambung pH Antasida, stres, H 2reseptor blocker usus motilitas Diare karena untuk penyakit penyerta,
makanan,
intoleransi disakarida, bayam Kadar makanan Lektin Phaseolus vulgaris (penghambatanglukosa
penyerapandan transportasi) Daerah permukaan usus halus Sindrom usus besar Darah dalam usus Alkohol Aliran getah bening usus Tripalmitin Sirkulasi enter
Chlordecanone (dicegah oleh cholestyramine) Permeabilitas mukosa Penyakit radang usus, penyakit seliaka Penghambatanpencernaan
proses
berpengaruh pada saluran GI, dan apakah mereka diserap atau mempengaruhi penyerapan zat lain sangat penting untuk memahami toksikologi makanan dan
Beberapa faktor yang dapat memengaruhi penyerapan GI dan laju penyerapan tercantum dalam Tabel 30-4.
STANDAR KESELAMATAN UNTUK MAKANAN, BAHAN MAKANAN, DAN KONTAMINAN
Undang-undang FD&C Menyediakan Pendekatan yang Praktis
Undang-undang FD&C menganggap bahwa makanan yang dikonsumsi secara tradisional aman jika tidak bebas dari kontaminan. Agar FDA melarang maka
memiliki bukti yang jelas bahwa kematian atau penyakit dapat ditelusuri dari konsumsi makanan tertentu. Fakta bahwa makanan mengandung banyak zat alami, b
beracun pada konsentrasi tinggi, dengan sendirinya tidak cukup berdasarkan Undang-Undang untuk menyatakan makanan tidak layak untuk dikonsumsi manusia
ini termasuk penerimaan status Umumnya Diakui Sebagai Aman (GRAS) dan penerapan toleransi.
Penerapan Pengalaman: Umumnya Diakui Aman (GRAS) Undang-undang FD&C mengizinkan penambahan zat ke dalam makanan untuk mencapai efek te
tersebut ditentukan sebagai GRAS. Undang-undang tidak mewajibkan FDA untuk membuat keputusan ini, meskipun tidak mengecualikan agen dari membuat k
Undang-undang tersebut sebaliknya mensyaratkan bahwa para ahli ilmiah mendasarkan penentuan GRAS pada kecukupan keselamatan, seperti yang ditunjuk
ilmiah atau melalui pengalaman berdasarkan penggunaan umum dalam makanan sebelum 1 Januari 1958, di bawah kondisi yang dimaksudkan penggunaan zat
201 (s)].
Selain memungkinkan zat-zat GRAS ditambahkan ke dalam makanan, Undang-Undang ini menyediakan kelas zat yang diatur zat aditif makanan, yang didef
apa pun yang digunakan untuk tujuan yang menghasilkan zat-zat tersebut. . . makanan apa pun. . . jika zat seperti itu tidak dikenal secara umum ... aman. ”Oleh
Katekin teh yang menghambat sukuk dan karenanyaglukosa
penyerapanTerapi obat bersamaan Garam besi / tetrasiklin
SUMBER: Dimodifikasi dari Hoensch HP, Schwenk M: Penyerapan usus dan metabolisme xenobiotik pada manusia, dalam Schiller CM (ed): Intox Toxicology. New York: Raven Press, 1984, hlm. 169–192.
Williams & Wilkins.
BAB 30 TOKSIKOLOGI MAKANAN 1195
perbedaan hukum diambil antara aditif makanan diatur dan zat GRAS. Aditif makanan yang diregulasi harus disetujui dan diatur sesuai dengan kondisi penggunaa
oleh FDA di bawah 21 CFR 172–179 sebelum dapat dipasarkan. Di bawah bagian 409 Undang-Undang, persyaratan data untuk mendukung penggunaan aditif m
dijelaskan secara umum. Persyaratan atau metode yang direkomendasikan untuk menetapkan kondisi aman penggunaan aditif tersedia dalam bentuk pedoman y
FDA. Pedoman ini, disebut sebagai Redbook, memberikan substansi dan definisi ke standar keamanan yang berlaku untuk bahan tambahan makanan yang dia
masuk akal tidak ada bahaya dalam kondisi penggunaan yang dimaksudkan" (Burdock dan Carabin, 2004).
Penggunaan Toleransi Jika makanan mengandung tidak dapat dihindari kontaminan yangbahkan dengan menggunakan praktik manufaktur yang baik saat i
dinyatakan tidak layak sebagai makanan jika kontaminan dapat membuat makanan yang membahayakan kesehatan. Dengan demikian, agar makanan itu sen
layak, itu harus biasanya merugikan, sementara kontaminan yang tidak dapat dihindari dalam makanan hanya perlu menimbulkan risiko bahaya bagi makanan y
layak, dan tunduk pada tindakan FDA. Alasan dikotomi adalah kepraktisan. Kongres mengakui bahwa jika otoritas diberikan untuk melarang makanan tradi
yang melampaui bukti yang jelas membahayakan kesehatan, badan tersebut akan mendapat tekanan untuk melarang makanan tertentu.
Makanan yang mengandung kontaminan yang tidak dapat dihindari tidak dilarang secara otomatis karena makanan tersebut tunduk pada ketentuan bagian 406
FD&C, yang menunjukkan bahwa jumlah kontaminan yang tidak dapat dihindari dalam makanan mungkin dibatasi oleh peraturan untuk perlindungan keseh
bahwa setiap jumlah kontaminan yang melebihi batas tetap akan dianggap tidak aman. Otoritas ini telah digunakan oleh FDA untuk menetapkan batasan jum
tidak dapat dihindari dalam makanan dengan peraturan (toleransi) atau oleh tingkat tindakan informal yang tidak memiliki kekuatan hukum. Tingkat tinda
ditetapkan untuk aflatoksin, fumonisin, dan patulin (Tabel 30-5). Level tindakan memiliki keuntungan menawarkan fleksibilitas yang lebih besar daripada
toleransi yang ditetapkan oleh regulasi. Apakah toleransi atau tingkat tindakan diterapkan pada kontaminan makanan yang tidak dapat dihindari, F
menyeimbangkan risiko kesehatan yang ditimbulkan oleh kontaminan yang tidak dapat dihindari terhadap hilangnya sebagian pasokan makanan. Sebaliknya
makanan yang dihindari oleh cGMP dianggap tidak aman di bawah bagian 406 jika merekapertimbangan-
Table30-5 FDA Aksi Tingkat untuk Mycotoxins
KOMODITI TINGKAT, ng/g
Aflatoksin
Semua produk, kecuali susu, yang ditunjuk untuk
manusia
ered beracun atau merusak. Dalam keadaan seperti itu, makanan biasanya dinyatakan tercemar dan tidak layak dikonsumsi manusia. Sejauh mana konsumen
makanan tersebut harus waspada tergantung pada risiko kesehatan yang ditimbulkan oleh makanan yang terkontaminasi. Jika ada kemungkinan yang masuk aka
atau paparan makanan semacam itu akan menyebabkan konsekuensi kesehatan yang serius atau kematian, FDA akan mencari Kelas I recall yang memberik
maksimum, kedalaman penarikan terbesar, dan kebanyakan tindak lanjut. Kelas II dan III menunjukkan risiko kesehatan yang semakin sedikit dan membu
peringatan publik, lebih sedikit pengingatan, dan lebih sedikit tindak lanjut (21 CFR 7.3).
Aditif Makanan dan Warna Bahan yang
sengaja ditambahkan, tidak dianggap GRAS, dapat berupa aditif makanan langsung atau aditif warna. Seperti halnya semua bahan yang ditambahkan secara tid
makanan, harus ada fungsi yang spesifik dan dapat dibenarkan. Sementara aditif warna hanya memiliki satu fungsi, aditif makanan mungkin memiliki salah satu
30-6).
Istilah "aditif warna" mengacu pada bahan yang merupakan pewarna, pigmen, atau zat lain yang dibuat melalui proses sintesis atau diekstraksi dan diisolas
hewan, atau mineral [Undang-Undang K&P 201 (t)]. Kulit hitam, putih, dan abu-abu antara juga termasuk dalam definisi ini. Ketika zat tambahan seperti i
diaplikasikan pada makanan, obat-obatan, atau kosmetik atau ke dalam tubuh manusia, mereka dapat memberikan warna. Aditif warna tidak memenuhi syarat unt
dua jenis zat tambahan warna yang telah disetujui untuk penggunaan makanan: yang membutuhkan sertifikasi oleh ahli kimia FDA dan yang dibeba
Sertifikasi, yang didasarkan pada analisis kimia, diperlukan untuk setiap batch dari sebagian besar warna organik yang disintesis karena mungkin mengandung k
bervariasi dari batch ke batch. Kebanyakan warna bersertifikat yang disetujui untuk penggunaan makanan mengandung awalan FD&C. Sertifikasi melib
mendalam tentang komponen utama dan jejak setiap batch aditif warna individual oleh ahli kimia FDA dan diperlukan sebelum bets apa pun dapat dirilis untuk pe
Aditif warna tersebut terdiri dari amina aromatik atau struktur azo aromatik (FD&C Blue No. 1, Blue No. 2, Green No. 3, Red No. 3, Red No. 40, Yellow No.
yang tidak dapat disintesis tanpa berbagai pengotor. Orange B dan Citrus Red No. 2 adalah satu-satunya warna makanan bersertifikat yang tidak memiliki pe
CFR 74 Sub Bagian A).
Terlepas dari kenyataan bahwa amina aromatik umumnya dianggap zat yang relatif beracun, warna FD&C terutama tidak beracun. Tabel 30-7, yang diadopsi da
Academy of Sciences (NAS) Nasional (Komite Perlindungan Pangan, 1971), menunjukkan bahwa warna makanan bersertifikat memiliki tingkat toksisitas yan
20
Alasan utamanya meliputi sulfonasi amina aromatik atau senyawa azo yang merupakan zat tambahan warna.asam sulfonat seperti itu
Aflatoksin: Susu 0,5 Patulin: Jus apel 50 Deoxynivalenol (DON atau vomitoxin): Semua
produk gandum yang dapat dikonsumsi olehmanusia
kelompoksangat polar, yang, dikombinasikan dengan berat molekul tinggi, mencegahnya diserap oleh Saluran GI atau sel yang masuk. Semua warna makan
secara luas di semua tes Tingkat Kepedulian (CL) III (Tabel 30-8) dan telah terbukti 'sangat' tidak beracun.
Warna makanan yang dikecualikan dari sertifikasi biasanya tidak dikenai persyaratan pengujian yang luas. Warna makanan yang dibebaskan terutama beras
Sementara warna makanan sintetis telah menerima mayoritas perhatian publik, ilmiah, dan peraturan, zat warna alami juga merupakan kelas yang pen
tambahan warna telah diberikan pengecualian dari sertifikasi di 21 CFR 73. Agen
Fumonisins, Total (FB1 + FB2 + FB3)
Produk jagung giling kering degermed 2000 jagung yang dibersihkan ditujukan untuk popcorn 3000 jagung yang dibersihkan untuk masa produksi 4000
SUMBER: Mycotoxins dalam Makanan Domestik (http://www.cfsan.fda.gov/∼comm /
cp07001.html)
1196 UNIT 7 APLIKASI TOXICOLOGY
Tabel 30-6 Bahan Tambahan Makanan Langsung Menurut Fungsi
NUMBERURAIAN URAIAN Contoh

makanan dengan
DESAINASIGAMBAR 170.3 (o) (1) Agen anti pembuatan memperlambat kemunduran, tengik, atau perubahan warna
dan agen karena oksidasi.
aliran bebas Butylated hydroxyanisole (BHA),
Zat yang ditambahkan ke produk makanan bubuk atau kristal butylated hydroxytoluene (BHT), propyl gallate
halus untuk mencegah caking, lumping, atau aglomerasi
Glucitol, sodium ferrocyanide,
(4) Warna dan zat warna tambahan Bahan yang digunakan
Glucitol, sodium ferrocyanide,
untuk menanamkan, melestarikan, atau, pengawet
silikon dioksida
meningkatkan warna atau naungan makanan, termasuk
silikon dioksida
penstabil warnawarna, zat penahan warna
FD&C Kuning No. 5 (tartrazine), FD&C Merah No. 4, β-
karoten, annatto, kunyit
(2) Agen antimikroba Zat yang digunakan untuk
mengawetkan makanan dengan
mencegah pertumbuhan mikroorganisme dan pembusukan (5) Agen pengawet dan pengawet Zat yang memberikan
selanjutnya, termasuk fungistat, kapang, dan penghambat tali rasaunik
dan efek yang terdaftar oleh NAS / NRC di bawah “pengawet”
dan / atau warna yangpada makanan, biasanya menghasilkan
Nisin; metil—, etil—, propil—, atau
peningkatan masa simpan
butil-ester dari pasam—hidroksibenozoat; natrium benzoat; Kalsium klorida , glucitolPenguat
asam sorbat dan garamnya
(3) Antioksidan Zat yang digunakan untuk mengawetkan (6)adonan Zat yang digunakan untuk memodifikasi pati dan
gluten, menghasilkan adonan yang lebih stabil, termasuk efek (10) Firming agents Substances added to precipitate residual
yang berlaku yang terdaftar oleh NAS / NRC di bawah pectin, strengthening the supporting tissue and preventing its
"pengkondisi adonan" collapse during processing
Kalsium bromat, ekstrak ragi roti, kalsium karbonat Calcium acetate, calcium
carbonate
(7) Bahan pengering Zat denganmenyerap air yang (11) Flavor enhancers Substances added to supplement,
kemampuandigunakan untuk menjaga lingkungan dengan enhance, or modify the original taste and/or aroma of a food
kelembaban rendah without imparting a characteristic taste or aroma of their own
Kalsium stearat, kobalt kaprilat,
Monosodium glutamate, inositol
kobalt tinggi
(8) Pengemulsi dan garam pengemulsi Zat yang mengubah

tegangan permukaan
pada komponen fase emulsi untuk membentuk dispersi atau (12) Flavor agents and adjuvants Substances added to impart
emulsi yang seragam. or help
Ester fosfat dari mono dan impart a taste or aroma in food
digliserida, monogliserida asetat, kalsium stearat Cinnamon, citral, p-cresol,
thymol, zingerone
(9) Enzim Enzim yang digunakan untuk
meningkatkanmakanan (Continued)
pemrosesandan kualitas makanan jadi

Papain, rennet, pepsin
CHAPTER 30 FOOD TOXICOLOGY 1197
Table 30-6 (Continued)
NUMBER DESIGNATION DESCRIPTION EXAMPLES
(13) Flour-treating agents Substances added to milled flour at the mill to (16) Humectants Hygroscopic substances incorporated in food to promote retention of m
improv e its color an/orincluding
baking qualities,
moisture-retention agents and antidusting agents
including bleaching and maturing agents Arabic gum, calcium chloride
Calcium bromate
(14) Formulation aids Substances used to promote or produce a (17) Leavening agents Substances used to produce or stimulate
desired physical state or texture in food, production of carbon dioxide in bake
including carriers, binders, fillers, to impart a light texture, including ye
plasticizers, film formers, and tableting aids foods, and calcium salts listed by the
Palm kernel oil, tallow NAS/NRC under “dough conditioner
Carbon dioxide, adipic acid
(15) Fumigants Volatile substances used for controlling insects

or pests
Aluminum phosphide, potassium (18) Lubricants and release agents Substances added to food contact surfaces to
bromide prevent ingredients and finished prod
from sticking to them
Mineral oil, acetylated monoglycerides
(19) Nonnutritive sweeteners Substances having less than 2% of the caloric peroxide
value of sucrose per equivalent unit of
sweetening capacity
Acesulfame, aspartame, saccharin
(23) pH control agents Substances added to change or maintain active

acidity or basicity, including buffers,
(20) Nutrient supplements Substances that are necessary for the body's alkalis, and neutralizing agents
nutritional and metabolic processes Acetic acid, propionic acid, calcium
Calcium carbonate acetate, calcium carbonate, carbon
dioxide
(21) Nutritive sweeteners Substances that have greater than 2% of the (24) Processing aids Substances used as manufacturing aids to
caloric value of sucrose per equivalent unit enhance the appeal or utility of a food
of sweetening capacity food component, including clarifying
Lactitol, hydrogenated starch agents, clouding agents, catalysts,
hydrolysate flocculents, filler aids, and crystalliza
inhibitors
Carbon dioxide, ammonium carbonate,
(22) Oxidizing and reducing agents Substances that chemically oxidize or reduce ammonium sulfate, potassium
another food ingredient, producing a more bromide
stable product, including the applicable
effects listed by the NAS/NRC under
“dough conditioners”
Calcium peroxide, chloride, hydrogen
1198 UNIT 7 APPLICATIONS OF TOXICOLOGY
Table 30-6 (Continued)
(25) Propellants, aerating agents, and gases Gases used to (28) Sta bilizers and thickeners Substances used to produce
supply force to expel a viscous solutions or dispersions, to impart body, improve
product or reduce the amount of oxygen in contact with the consistency, or stabilize emulsions, including suspending and
food in packaging bodying agents, setting agents, jellying agents, and bulking
Carbon dioxide, nitrous oxide agents
Calcium acetate, calcium carbonate
(26) Sequestrants Substances that combine with

polyvalent metal ions to form a soluble metal complex to
improve the quality and stability of products
Acetate salts, citrate salts, gluconate salt, metaphosphate,
edetic acid, calcium acetate (29) Surface-active agents Substances used to modify surface
properties of liquid food components for a variety of effects
other than emulsifiers but including solubilizing agents,
(27) Solvents and vehicles Substances used to extract or dispersants, detergents, wetting agents, rehydration enhancers,
dissolve whipping agents, foaming agents, and defoaming agents
another substance Sorbitan monostearate, mono- and
Acetic acid, acetylated diglycerides, polysorbate 60, acetostearin
monoglycerides
(30) Surface-finishing agents Substances used to increase of a variety of natural compounds generally obtained by various
palatability, extraction and treatment technologies. Included in this group of
preserve gloss, and inhibit discoloration of foods, including colors are preparations such as dried algae meal, beet powder,
glazes, polishes, waxes, and protective coatings grape skin extract, fruit juice, paprika, caramel, carrot oil,
Ammonium hydroxide, arabic gum cochineal extract, ferrous gluconate, and iron oxide. A
problem encountered in attempts to regulate these additives is
the lack of a precise chemical definition of many of these
preparations. With a few exceptions such as caramel, which is
the most widely used color, the natural colors have not been
heavily used. In part, this may be due to economic reasons, but
(31) Synergists Substances used to act or react with these colors generally do not have the uniformity and
intensity characteristic of the synthetic colors, therefore
another food ingredient to produce a total effect different from
necessitat- ing higher concentrations to obtain a specific color
or greater than the sum of the effects produced by the
intensity. They also lack the chemical and color stability of the
individual ingredients
synthetic colors and have a tendency to fade with time.
Acetic acid, propionic acid
Intake of color additives varies among individuals. The max-
imal intake of food colors is estimated to be ∼53.5 mg/d,
whereas the average intake per day is ∼15 mg (Committee on
Food Protec- tion, 1971). Only about 10% of the food
consumed in the United States contains food colors. The foods
(32) Texturizers Substances that affect the appearance or that utilize food colors in order of the quantity of color utilized
are (1) beverages, (2) candy and
feel of food
Calcium acetate
Table 30-7 Data on Certified Food Colors Permanently Listed in the United States
NO ADVERSE ESTIMATED EFFECT DIETARY MAXIMUM LEVELS AND SAFE LEVEL FOR INGESTION COLOR ANIMALSTUDIES
FD&C Blue No.1 5.0% rats 363 1.23

2.0% dogs FD&C Blue No. 2 1.0% rats, dogs 181 0.29 FD&C Green No. 3 5.0% rats 181 0.07
1.0% dogs 2.0% mice Orange
1.0% dogs 5.0% mice Citrus Red No. 2 0.1% rats 18 Not applicable FD&C Red No. 3 0.5% rats 91 1.88
2.0% dogs 2.0% mice FD&C Yellow No.
2.0% dogs FD&C Yellow No. 6 2.0% rats 363 15.5
2.0% dogs 2.0% mice
SOURCE: Committee on Food Protection (1971). Reprinted with permission from (Food Colors) c (1971)
by the National Academy of Sciences, Courtesy of the National Academies Press, Washington, DC
Table 30-8 Summary of the Toxicity Tests Recommended for Different Levels of Concern1
CONCERN LEVELS
TOXICITY STUDIES 2 I II III
Short-term tests for genetic toxicity XXX Metabolism and pharmacokinetic studies XX Short-term (28-day) toxicity studies with
rodents
Methods Used to Evaluate the Safety of Foods, Ingredients, and Contaminants
Safety Evaluation of Direct Food and Color Additives The basic concept that forms the foundation for the safety evaluation of direct food and color additiv
that the safety of any added substance to food must be established on the basis of the intended conditions of use in food. Factors that need to be taken into ac
purpose for use of the
food to which the substance is added, (3) the concentration level used in the proposed foods, and (4) the population expected to consume Subchronic (90-day)
the substance. rodents
The evaluation of a new food additive is a complicated and expensive undertaking, especially when the additive will be widely used in many foods. Each addi
safety questions depending on its chemistry, stability in use, metabolism, toxicity study results, and estimated human exposure. Integral to a discussion of expo
the “whole food additive.” This refers to the additive, the degradation or conversion products arising from the use of the additive in foods, and the impurities found
additive itself (Kotsonis and Hjelle, 1991, 1996).
Exposure: The Estimated Daily Intake Prior to 1958, the FDA held to the philosophy that food additives (and potential contaminants) should not be harm
is impractical, as many substances critical to life are toxic at high doses. For example, distilled water is harmless if consumed at low amounts, but if enough
electrolyte imbalance, fatalities may occur. Other substances that may be toxic at high concentrations, such as acids or bases, are used at low concentrat
inhibit bacterial growth during the processing of meat
Subchronic (90-day) toxicity studies with
nonrodents
X3
Reproduction studies with teratology phase X3 X3 One-year toxicity studies with nonrodents X Carcinogenicity studies with rodents X 4 Chronic toxicity/carcino
with rodents
X4,5
1http://www.cfsan.fda.gov/∼redbook/redtoc93.html. 2 Not including dose range-finding studies, if appropriate. 3Including neurotoxicity and immunotoxicity screens. 4An in utero ph
for one of the two recommended carcinogenicity studies with rodents, preferably the study with rats. 5Combined study may be performed as separate studies.
confections, (3) dessert powders, (4) bakery goods, (5) sausages (casing only), (6) cereals, (7) ice cream, (8) snack foods, and (9) gravies, jams, jellies, and so
Food Protection, 1971).
Table 30-9 Food Categories
170.3(n) (1) Baked goods and
baking mixes
Includes all ready-to-eat and ready-to bake
products, flours, and mixes requiring preparation before serving
Doughnuts, bread, croissants, cake mix,
cookie dough
(2) Beverages, alcoholic Includes malt beverages, wines, distilled
liquors, and cocktail mix
Beer, malt liquor, whiskey, liqueurs, wine
coolers (3) Beverages and
beverage bases, nonalcoholic
Includes only special or spiced teas, soft
drinks, coffee substitutes, and fruit- and vegetable-flavored gelatin drinks
Herbal tea (non-tea-containing “teas”), soda
pop, chicory
(4) Breakfast cereals Includes ready-to-eat and instant and regular
hot cereals
Oatmeal (both regular and instant), farina,
corn flakes, wheat flakes
are considered GRAS by the FDA. These examples underscore the fact that exposure level is a major factor in a safety evaluation, and is reflected in the
Principles for the Safety As- sessment of Direct Food Additives and Color Additives Used in Food (FDA, 1982a),2 a source used to determine which testin
conducted to determine safety levels of a substance.
In food additive safety determinations, exposure is usually referred to an estimated daily intake (EDI) and is based on the daily intake (I) of the food in which
used, and the concentration (C) of the substance when it is in the food. Many food ingredients are used in several different food categories, but as an example,
an additive is used only in breakfast cereals. If the substance is added at a concentration that does not exceed 20 μg/g (ppm), and the mean daily intake of bre
g/person/day, the EDI is calculated at 3500 μg/person/day. As most food additives are used in many foods, the total exposure is the sum of the exposures fr
categories. The formula for exposure to food additive B is
EDIB = (CBf × If) + (CBg × Ig) + (C...)
where CBf and CBg are the concentration of B in food category f and g, respectively. Ifand Ig are the daily intake of food category f and g, respect
EDI is the sum of the individual contributions of B in each of the food categories.
The same principles may be applied to the estimation of the consumption of residue from secondary direct additives (substances not intended to remain in a fo
effect has been accomplished; examples include solvents, sanitizers, and defoaming agents), and contaminants. Additional information on the estimation
food additives and contaminants has been made available by the agency's Center for Food Safety and Applied Nutrition. 3
Calculating the EDI raises several basic questions: (1) How does one determine the amount of a food additive that is added to
2 The Agency is in the process of updating the Redbook and is now making Redbook 2000 chapters available electronically (http://www.cfsan.fda.gov/∼redbook/red-to
2000 chapters now substitute for, or supplement, guidance available in the 1982 Redbook I and in the 1993 Draft Redbook II, which can be obtained from the Office of Fo
additional chapters of Redbook 2000 are completed they will become available electronically. 3 US FDA, Center for Food Safety and Applied Nutrition, Of- fice
September, 1995, available online at http://www.cfsan.fda.g
each food category? and (2) How are food categories determined? To determine the amount of food additive added to each food category, the highest end of th
for the new substance is used. These food group maximums are not to be exceeded by a food manufacturer, based on the current Good Manufacturing Prac- tice
21 CFR 110), which binds a manufacturer not to add more of an additive than is reasonably required to achieve the specific technical effect of the food additive
tion on cGMPs may be found in the Food Chemicals Codex (FCC, 2003). General food categories have been specified by the FDA. A sample of the cate
Table 30-9. These categories were derived from a survey of food additives conducted by the National Academy of Sciences/National Research Council an
(NRC/NAS, 1979). This survey pioneered the use of categorizing foods, but changes in the consumption patterns of the US population, in addition to changes
available, have necessitated the generation of additional, more current data.More contemporary data on food intake has been calculated through the use
surveys (Table 30-10). Food consumption databases have specific characteristics and are based on particular assumptions. Methods commonly used by
manufacturers, nutritionists, and general researchers for assessing food consumption by individuals include 24-hour dietary recalls, dietary records, food fre
dietary history accounts (Matulka, 2005). For example, one database may be based on an individual's food intake from the past 24 hours, while another may u
taken over a three-day period of time, and yet another may cover average consumption over 14 days. Some databases may provide only general population
while others may provide a detailed breakout of particular subpopulations (eg, the elderly, women, teenagers).
In safety assessments, one must consider other sources of consumption for the proposed intended use of the food additive, such as whether it is already use
purpose, is used in nonfood products (eg, toothpaste, lipstick, drugs), or the additive occurs naturally in foods. In summary, to estimate human consumption
substance, it is necessary to know (1) the levels of the substance in food, (2) the daily intake of each food containing the substance, (3) the distribution of fo
population, and (4) the potential exposure to the substance from nonfood sources (Tennant, 2002).
Table 30-10 Databases for Estimating Food Intake

to CL II. In contrast, the same dose (ie, 0.03 ppm) of a substance in Structure Category A would be assigned to the lesser CL I.
Continuing Survey of Food Intakes by Individuals, USDA, 1985,

1986, 1989, 1990, 1991 The Nationwide Food Consumption Survey, USDA, 1987–1988* Estimates of Daily Intake (NRC/NAS), 1979 (Abrams, 1992) The
Study (Pennington and Gunderson, 1987) Foods Commonly Consumed by Individuals, USDA (Pay et al.,
1984) USDA Economic Research Service Reports Continuing Survey of
Food Intakes by Individuals, USDA, 1985, 1986, 1989*, 1990, 1991 National Health and Nutrition Examination Survey I, II, III,
2001–2002, 2003–2004 What We Eat In America, USDA 2001–2002
∗ Indicates current use by FDA. SOURCE: (R. Matulka, personal communication). Reprinted with permission from (The 1977 Survey of the Industry on the Use of Food Additives) c (1979) by the National A
of the National Academies Press, Wash- ington, DC
Before a food additive is approved, evidence is required by regulatory agencies that indicate the additive is safe for its intended use(s) and that the EDI for
its acceptable daily intake (ADI) (Butchko and Kotsonis, 1996). Regulatory agencies may impose restrictions on certain uses of food additives if the EDI exceeds the
approvals for new categories of use. Chronic, long-term rodent toxicity studies are usually used in determining the ADI. These studies are used to determine the no- o
level (NOAEL) for the additive. To provide an adequate level of safety from animal to human extrapolation, a 100-fold safety factor is usually employed to account f
and the inter-individual variation among humans, to determine the ADI for a food additive. This factor provides a reasonable certainty in estimating safe doses i
studies (Lehman and Fitzhugh, 1954).4
Assignment of Concern Level (CL) and Required Testing Structure–activity (SA) relationships are now the basis for developing many therapeutic drug
additives. These relationships are put to good use in the Toxicological Principles for the Safety Assessment of Direct Food Additives and Color Addi- tives Used in
which describes a qualitative “decision tree” that assigns categories to substances on the basis of the structural and functional groups in the molecule. Additives
with a high order of toxicity are assigned to category C, those of unknown or intermediate toxicity are assigned to category B, and those with a low potential for
category A. For example, a simple saturated hydrocarbon alcohol such as pentanol would be assigned to category A. Similarly, a substance containing an α,
function, epoxide, thiazole, or imidazole group would be assigned to category C. Thus, based on structure assignment and calculated exposure, the Concern Lev
(Table 30–11). For example, 0.03 ppm of a substance in Structure Categor
4 Thisis the source of the 100 safety factor.

Once the CL is established, a specific test battery is prescribed, as shown in Table 30-8. The tests for CL III are the most demanding and provide the
determination of adverse biological effects, including effects on reproduction. The tests are comprehensive enough to detect nearly all types of observable toxi- c
and benign tumors, preneoplastic lesions, and other forms of chronic toxicity. The tests for CL II are of intermediate breadth. These tests are designed to detect the
other than late-developing histopathological changes. The short-term (genotoxicity) tests are intended to identify substances for which chronic testing become
battery is the least broad, as is appropriate for the level of hazard which substances in this category may pose. However, if untoward effects are noted, addition
necessary. Studies of the absorption, distribution, metabolism, and elimination characteristics of a test substance are recommended before the initiation of toxicit
days' duration. Of particular importance for many proposed food ingredients is data on their processing and metabolism in the GI tract.
Unique to food additive carcinogenicity testing is the contro- versial use of protocols that include an in utero phase. Under such protocols, parents of test
the test substance for 4 weeks before mating and throughout mating, gestation, and lac- tation. Most countries and international bodies do not subscribe to the combin
with a rat carcinogenicity study, as this presents a series of logistical and operational problems and substantially increases the cost of conducting a rat carcinogen
began requesting in utero studies of the food industry in the early 1970s, when it was discovered from lifetime feeding studies that the artificial sweetener sacch
tumors in male rats when in utero exposure was introduced. Subsequently, the FDA required the food, drug, and cosmetic color industries to conduct lifetime carcino
of 18 color additives in rats using an in utero exposure phase.
Special note should also be made of genetic toxicity testing. Genetic toxicity tests are performed for two reasons: (1) to test chemicals for potential ca
assess whether a chemical may induce heritable genetic damage. Currently, genetic toxicity assays can be divided into three major groups: (1) forward and reverse m
mutations, deletions), (2) clastogenicity assays detecting structural and numerical changes in chromosomes (eg, chromosome aberrations, micronuclei), and (3) as
damage (eg, DNA strand breaks, unscheduled DNA synthesis).
Because the correlation between carcinogens and mutagens has proved to be less than desirable, as has been demonstrated by false–positive and false–
carcinogens and noncarcinogens have been examined in genetic toxicity tests, it is recommended that several tests be selected from a battery of tests. It should be
number of tests employed increases, the possibility of false-negative results increases as well. Consequently, the National Toxicology Program (NTP) has advised
mutational assay be used (Salmonella ty- phimurium) to optimize the prediction of carcinogenicity (Tennant and Zeiger, 1993).
Safety Determination of Indirect Food Additives Indirect food additives are food additives that are not added directly to food but
Table 30-11 Assignment of Concern Level
CONCERN STRUCTURE CATEGORY A STRUCTURE CATEGORY B STRUCTURE CATEGORY C LEVEL
<0.05 ppm in the total diet (<0.0012 mg/kg/day)
<0.025 ppm in the total diet (<0.00063 mg/kg/day)
<0.0125 ppm in the total diet
(<0.00031 mg/kg/day)
I
or or or ≥0.05 ppm in the total diet (≥0.0012 mg/kg/day)
≥0.025 ppm in the total diet (≥0.00063 mg/kg/day)
≥0.0125 ppm in the total diet
(≥0.00031 mg/kg/day)
II
or or or ≥1 ppm in the total diet (≥0.025 mg/kg/day)
III
enter food by migrating from surfaces that contact food. These surfaces may be from packaging material (eg, cans, paper, plastic) or the coating of packaging
used in processing, holding, or transporting food.
Essential to demonstrating the safety of an indirect additive are extraction studies with food-simulating solvents. The FDA recommends the use of three food-s
10% ethanol, 50% ethanol, and corn oil or a synthetic triglyceride—for aqueous and acidic, alcoholic, and fatty foods, respectively (FDA, 2002a). The con
depend in part on the intended conditions of use. Extraction studies are used to assess the level or quantity of a substance that might migrate and become a compo
to consumer exposure.
To convert extraction data from packaging material into anticipated consumer exposure, the FDA has determined the fraction of the US diet which comes into c
classes of material: glass, metal (coated and uncoated), paper (coated and uncoated), and polymers. For each class, the FDA has assigned a “consumption facto
fraction of the total diet that comes into contact with an individual class of material.
The fraction of individual food types (aqueous, acidic, alcoholic, fatty) for which such packaging material is used is referred to as the food-type-distribution fact
cumulative estimated daily intake (CEDI), the following equation is used:

CEDI = CF × [(fT aqueous + fT acidic) × (ppm of migrating substance
in 10% ethanol) + (fT alcoholic × ppm of migrating substance in 50% ethanol) + (fT fatty × ppm of migrating substance in corn oil)] × 3 kg/person/day = mg/pe
For additives with virtually no migration (<0.5 ppb), in which the CEDIs correspond to 1.5 μg/person/day, no safety studies are recommended. Migration leve
extraction studies, that are greater than 0.5 ppb to 50 ppb (150 μg/person/day), in vitro genotoxicity tests should include bacterial mutagenicity and cytog
chromosomal damage using mammalian cells or an in vitro mouse lymphoma assay. Where there is significant migration, ie, 50 ppb to 1 ppm (3 mg/person/d
tests should be conducted and the substance should be further evaluated by two subchronic oral toxicity studies (one in a rodent species
5 The 3 kg is FDA's value for daily food consumption which, when multiplied by mg/kg (ppm) and the weighting factors, reduces to milligrams of the additive per day.
and one in a nonrodent species). The studies should provide an adequate basis for determining an acceptable daily intake (ADI) for the indirect additive o
indicated range of CEDIs. In addition, the results of these studies will help determine whether longer-term or specialized safety tests (eg, metabolism studies, te
reproductive toxicity studies, neurotoxicity studies, and immunotoxicity studies) should be conducted to assess the safety of these substances. For cumulative e
1 ppm, FDA recommends submission of a food additive petition (FDA, 2002a).
Safety Requirements for GRAS Substances In spite of the fact that the FD&C Act and the relevant regulations scrupulously avoid defining food except in
“food means articles used for food or drink for man or other animals. . . [and includes] chewing gum, and...articles used for components of any such article”
GRAS when they are added to other food, for example, green beans in vegetable soup (Kokoski et al., 1990; Burdock and Carabin, 2004). It also regards a numbe
as GRAS, and these ingredients are listed under 21 CFR 182, 184, and 186. However, the language used acknowledges that there are substances the FDA co
which are not listed. This accomplishes two things: (1) It leaves the door open for additional nonlisted substances to be affirmed as GRAS by the agency a
concept that substances can be deemed GRAS whether or not they are listed by the FDA or on a publicly available list. A list of examples of substances regard
in Table 30-12. It is important to re-emphasize that GRAS substances, though used like food additives, are not food additives. Although the distinction ma
semantics, it allows GRAS substances to be exempt from the premarket clearance restrictions enforced by the FDA and exempt from the Delaney carcino
that clause of the Act pertains only to food additives.6
While the courts have ruled that GRAS substances must be supported by the same quantity and quality of safety data that support food additives, this does n
must be identical in nature and character to those for a food additive. For uses of substances to be eligible for classification as GRAS, there must be common kn
the scientific community about the safety of substances directly or indirectly added to food (21 CFR
6 See Assessment of Carcinogens.
Table 30-12 Examples of GRAS Substances and Their Functionality
CFR NUMBER SUBSTANCE FUNCTIONALITY
Substances Generally Recognized as Safe 21 CFR 182 182.2122 Aluminum calcium silicate Anticaking agent
182.8985 Zinc chloride Nutrient supplement
Direct Food Substances Affirmed as Generally Recognized as Safe 21 CFR 184 184.1005 Acetic acid Several 184.1355
Helium Processing aid
Indirect Food Substances Affirmed as Generally Recognized as Safe 21 CFR 186 186.1025 Caprylic acid Antimicrobial
186.1374 Iron oxides Ingredient of paper and paperboard
applications. Many substances, for example, that are used in food
processing have never received formal FDA approval. The use of these
170.30); this is termed the “common knowledge standard” by FDA. 7 substances in the manufacture of food products is considered
The studies relied on for concluding that a given use of a substance is appropriate under cGMPs, while the substance itself is considered
GRAS ordinarily are based on generally available data and infor- GRAS for such purposes. Similarly, certain substances are permitted
mation published in the scientific literature. Such data are unlikely to as optional ingredients in standardized foods [foods with standards of
be conducted in accordance with FDA-recommended protocols, as identity specified by regulation (21 CFR 130-169)] even though they
these studies often are conducted for reasons unrelated to FDA are not approved food additives and are not on any of the GRAS
approval. Thus, the first basis for a GRAS determination is by “sci- lists.The GRAS concept as traditionally applied in the United
entific procedures” (ie, test data). GRAS status also can be based on
experience with common use in food before January 1, 1958,8 which States also has applicability to certain novel foods which may differ
further distinguishes GRAS data requirements from those de- manded only slightly from traditional foods or which, after careful
of food additives. Such experience need not be limited to the United consideration, can be regarded as raising no issues or questions of
States, but if it comes from outside the United States, it must be safety beyond
published or corroborated by an independent source. The FDA has
made it clear, that while an ingredient may have an extensive history
of use prior to 1958, this does not place it beyond regulatory reach, as 7 http://www.cfsan.fda.gov/∼rdb/opa-g092.html (site visited 10 April
new data generated must be taken into account—new data trumps
2006). 8 There are some exceptions to this rule. In at least one case,
history of use.9
FDA has indicated that use before 1958 was not sufficient to demonstrate
safety. (See GRAS Notice No. GRN 00040 on mineral oil).
Importance of the GRAS Concept
http://www.cfsan.fda.gov/∼rdb/opa-g040.html, site visited 9 April 2006). 9
The importance of the GRAS provision is obvious from its many http://www.cfsan.fda.gov/∼rdb/opa-g071.html (site visited 10 April
2006). to certain caterpillar insect pests that destroy corn plants (EPA, 1988;
that raised by the traditional foods they are intended to replace. The McClintock et al., 1995). By enabling the corn plant to protect itself
GRAS approach may therefore permit the introduction of novel foods from this insect pest, the use of this product can reduce the need for
that contain less saturated fat and/or cholesterol or more fiber or are in and use of conventional insecticides (Gianessi and Carpenter, 1999).
other ways modified. Irrespective of the breeding method used to produce a new
plant variety, tests must be done to ensure that the levels of nutrients
Transgenic Plant (and New Plant Varieties) Policy Crops have been or toxins in the plants have not changed and that the food is still safe to
genetically modified using conventional breeding methods for more consume. For food/feed from biotechnology-derived crops,
than a hundred years to produce new plant varieties with improved compositional analyses are done to ensure that the levels of key
characteristics. Methods such as wide crosses of distantly related nutrients or toxins are comparable to food from conventional varieties.
species that normally would not interbreed and mutagenesis of This is also done for a few conventionally bred crops where levels of
developing seeds using radiation or chemical mutagens have been important toxins such as glyoalkaloids in potatoes and erucic acid in
successfully employed to produce genetic variation for selection of rapeseed oil have been monitored. The Interna- tional Life Sciences
improved plant varieties. Over the past decade, scientists have em- Institutes (ILSI, 2006) supports a large crop composition database that
ployed biotechnology to add one or more specific genes into crops like provides information on the natural vari- ability in composition for
soybean, corn, cotton, and canola, to improve pest and disease conventional corn, soybean, and cotton crops. This database provides
management, resulting in agronomic, economic, environmental, a reference for comparing the nutrient composition of new crop
health, and social benefits for farmers (Brooker and Barfoot, 2005; varieties (Taylor et al., 1999; George et al., 2004; Herman et al., 2004;
James, 2006). For example, much of the corn crop planted in the United Oberdoerfer et al., 2005). Animal feeding studies are also done with
States contains a gene from the bacterium Bacillus thuringiensis that biotechnology-derived crops fed over several weeks to months to a
produces a Bt insecticidal protein (James, 1999). Bt is a protein toxic variety of farm animal species
to substances commonly found in food, a food additive petition
may have to be filed.The Federal Register notice offers
to ensure that the performance (feed efficiency, milk points of consideration for the safety assessment of new
production, etc.) is comparable to that of conventional controls
plant varieties (Table 30-13). Accom- panying these points of
(Flachowsky et al., 2005). Food safety studies have also been
consideration are a decision flowchart and advice that the FDA
done with various biotechnology-derived crops to ensure that
be consulted on certain findings, for example, transference of
there are no treatment- related adverse findings (Brake and
allergens from one plant to another, a change in the
Evenson, 2004; Hammondet al., 2005; MacKenzie et al., 2005).
concentration or bioavailability of nutrients, and the
Clearly, new proteins produced in plant varieties must be
introduction of a new macroingredient.
nontoxic and not have the characteristics of proteins known to
cause allergies. Thus, the proteins produced in genetically In the United States new plant varieties are regulated not only
modified crops are evaluated for toxicity (Sjoblad et al., 1992; by the FDA, but also by the Environmental Protection Agency
Harrison et al., 1996; Betz et al., 2000; Pariza and Johnson, (EPA) and US Department of Agriculture (USDA). The FDA
2001) and allergenicity (Metcalf et al., 1996; Astwood et al., is responsible for the safety and labeling of foods and feeds
2003). The DNA that is introduced into genetically modified derived from crops, irrespective of the method used to produce
plants to direct the production of such new proteins has been the new plant variety. The EPA is responsible for assuring the
determined to be Generally Recognized As Safe (FDA, 1992). safety of pesticides, thus in the example cited above whereby a
pesticide is produced in a new plant variety, this product would
The safety of new plant varieties (transgenic plants, geneti-
also fall under EPA's juris-
cally modified plants) is regulated primarily under the FDA's
post- market authority [section 402(a)(1) of the FD&C Act].
This section, previously applied to occurrences of unsafe Table 30-13 Points of Consideration in the Safety
levels of toxicants in food, is now applied to new plant varieties
Assessment of New Plant Varieties
whose composition has been altered by an added substance. The
new policy has been applied to plants containing substances Toxicants known to be characteristic of the host and donor
that are GRAS [Federal Reg- ister 57(104): 22984–23005]. The species The potential that food allergens will be transferred
Federal Register notice (May 29, 1992) indicates that “[i]n from one food
most cases, the substances expected to become components of source to another The concentration and bioavailability of
food as a result of genetic modification of a plant will be the important nutrients for
same as or substantially similar to substances commonly found
which a food crop is ordinarily consumed The safety and
in food, such as proteins, fats and oils, and carbohydrates.”
nutritional value of newly introduced proteins The identity,
The notice also indicates the responsibility of the FDA to
composition, and nutritional value of modified
exercise the premarket review process when the “objective
characteristics of the substance raise questions of safety.” In carbohydrates or fats and oils
regard to substances within the new variety that are not similar diction. The USDA's Animal and Plant Health Inspection
Service has responsibility for the environmental safety of field- substantive part of the diet (estimated to constitute as much as
testing and commercial planting of new plant varieties. 15–20%). For example, a macroingredient substitute or food
The developer of a biotechnology-derived crop variety must projected to be consumed at a level of just 5% of the diet (150
obtain registration from not only the country of origin but from g/d) would require the test animal (rat) to consume 250 g/kg/d,
importing countries as well (OECD, 1993). A variety of Euro- or slightly more than the rat's body weight. This is an untenable
pean/Global Scientific authorities (WHO, 1995; FAO, 1996; test requirement, for at those levels, the investigator would
OECD, 1997; Codex, 2003; EFSA, 2004) have provided establish an effect level only for malnutrition, not for the
guidance on the safety assessment process for food and feed toxicity of the macroingredient. The converse is true for some
derived from biotechnology-derived crops. The process essential nutrients, such as vitamins A and D and iron, which at
considers two main categories of potential risks: those related doses 100 times the nutritional use level would be toxic
to the properties and function of the introduced protein(s), and (Kokoski et al., 1990). The answer therefore lies in careful
those related to the whole food crop since insertion of the interpretation of toxicological data and the conduct, where
introduced gene(s) into the plant genome theoretically could appropriate, of special studies to assess drug interactions,
cause unintended environmental effects. As in conventional nutrient interactions changes in gut flora, changes in gut
crop breeding, agronomic studies carried out under diverse activity, and the like (Munro, 1990; Borzel- leca, 1992a,b).
environmental conditions are used to screen for varieties that Also, it may be appropriate to consider what effect, if any,
exhibit unintended changes so they can be eliminated from macroingredients may have on individuals with compromised
development. digestive tracts, those dependent on laxatives, and those on
high- fiber diets.
The regulatory approval of a new food additive is generally
Methods for Establishing Safe Conditions of Use for Novel based on traditional toxicology studies. The rationale is that
Foods Novel foods, including those derived from new plant data from such studies will adequately predict adverse effects
varieties and macroingredient substitutes, present new that could occur in humans. However, such studies, especially
challenges and may require new methods of determining for novel foods, may not be adequate. Therefore, although
safety. For example, with each new additive, it has been human studies are not generally required for food additives, in
traditional (and rooted in a regulation such as 21 CFR 170.22) the case of novel foods, human studies are likely essential in
to establish an ADI, which is usually based on 1/100 of the evaluating their safety (Stargel et al., 1996).
NOEL established in animal testing. This works well for Another useful tool in ensuring the safety of a food additive is
additives projected to be consumed at a level of 1.5 g/d or less monitoring it after its approval, or postmarketing surveillance.
(which is equal to or less than 25 mg/kg), for this extrapolates With widespread use of a food additive, monitoring for
at a 100-fold safety factor to consumption by a rat at a level of consump- tioncan determine whether actual consumption
2500 mg/kg/d (about 5% of the rat's diet). The problem arises exceeds the EDI and
when a new food or macroingredient substitute becomes a
Although the GI tract is an organ for absorption, it is also
the first barrier to substances that we do not wish to absorb (eg, large
molecules such as colors) or serve their function best by not being
monitoring for anecdotal complaints may identify adverse health absorbed (eg, fiber). The question then arises as to what impact
effects that escaped detection in earlier studies. This could be espe- nanotechnology might have on this balance. Size has always mat- tered
cially important for novel foods when traditional toxicology studies are and in the range of what has been accepted as “nano”,10 many of the
not done at large multiples of the EDI (Butchko et al., 1994, 1996a).
principles of absorption (as well as distribution, metabolism, and
Thus, the combination of traditional toxicity studies, special animal and
excretion) may be affected (EPA, 2005). Further, a striking ob-
human studies, and possibly postmarketing surveillance will ensure the
servation regarding particle health effects is the ability of particles to
safety of consumers and provide evidence to justify a safety factor
generate toxic effects at the site of initial deposition as well as sig-
different from 100.
nificant systemic toxic responses (EPA, 2004). Another observation
that “size does matter” is that degraded carregeenan (MW 30,000) may
Nanotechnology Nanotechnology offers some distinct advantages in have carcinogenic properties,11 while undergraded carrageenan (MW
delivery systems using micelles and liposomes and other techno- 100,000) apparently does not. Also, food packaging can incor- porate
logical advantages as nanoemulsions (emulsion stability), biopoly-
the ultraviolet-blocking material, TiO2, but because titanium
meric nanoparticles (encapsulation technology), and cubosomes
(solubilize hydrophobic, hydrophilic, and amphiphilic molecules, dioxide's safety is predicated upon its lack of absorption (IFST, 2006b),
among other uses), thus allowing new and more efficient uses of old the use of nanotechnology may ultimately mandate a new safety
products. Nanotechnology can enhance solubility, facilitate con- review. Presently, the FDA has taken no action on nanotechnology,
trolled release, improve bioavailability, and protect labile substances as it prefers to regulate on a product-by-product basis and does not
(including micronutrients and bioactive substances) during process- regulate a technology.12
ing, storage, and distribution (Chen et al., 2006).
Safety Requirements for Dietary Supplements consumer's concessions were that (1) supplements could not be added
to food (because of the lower threshold for safety), (2) consumption
Dietary supplements have a special status within the law and the will always remain the product of an overt, voluntary act on the part
regulations—supplements are regarded as foods or food constituents of the consumer (a dietary supplement can never be represented as a
and not food additives, nor drugs. There is also a different standard of food or meal replace- ment), and (3) because the recommended daily
safety, the concept of reasonable expectation of no harm, although dose is presented on the supplement, the consumer will assume at least
articulated in the Federal Food Drug and Cosmetic Act (FFDCA) some risk15 from consumption (articulated by the standard of
definition of adulterated food (Section 402) as [no] “significant or reasonable expectation of no harm (21 CFR 190.6(a)16). As a final
unreasonable risk of illness or injury.”13 This is a lesser safety stan- safeguard, Congress em- powered the Secretary of Health and Human
Services HHS (not the Commissioner of FDA), to take action through
the “imminent hazard” clause of the regulation if a supplement is
10 A nonometer is one billionth of a meter (10−9 m)—about one ten- determined to have an unexpected consequence (Burdock, 2000;
thousandth of the diameter of a human hair, a thousand times smaller than a red Mackey and Kotsonis, 2002; Burdock et al., 2006).
blood cell, or about half the size of the diameter of DNA (EPA, 2005). 11
Degraded carrageenan is classified by the International Agency for Assessment of Carcinogens

Re- search on Cancer (IARC) as 2B, a possible human carcinogen, based on Carcinogenicity as a Special Problem Congress provided the FDA
animal study data. Native carrageenan has been classified by IARC as 3, with wide latitude in assessing safety and as suring a safe food supply
unclassifiable with respect to carcinogenicity in humans. 12 FDA Regulation with one exception. That exception is a provision of the FD&C Act
known as the Delaney clause, which prohibits the approval of
of Nanotechnology Products (http://www.fda.gov/ regulated food additives “found to induce cancer when ingested by man
nanotechnology/regulation.html) (site visited 9 April 2006). 13 Also
or animals” [sections 409(c)(3)(A), 706(b)(5)(B), and 512(d)(1)(H)].
The Delaney prohibition applies only to the approval of food
articulated in the FFDCA (§413) as “reasonably be expected to be additives, color additives, and animal drugs; it does not apply to un-
safe”. avoidable contaminants or GRAS substances or ingredients sanc-
dard than the reasonable certainty standard for substances added to tioned by the FDA or USDA before 1958. The clause also does not
foods. The basis for this rationale is that consumption of a dietary apply to constituents that are present in food or color additives or
supplement is by choice, not involuntary as for a food (ie, food must animal drugs, provided that the level of such contaminants can be
have a presumption of safety and therefore, the higher standard of demonstrated to be safe and the whole additive, including its
safety). Therefore, because there is (1) a deliberate choice involved in contaminants, is not found to induce cancer in humans or animals.
consuming a dietary supplement and (2) because the daily
recommended intake is clearly stated on the label, there is an implied
assumption of some risk on the part of the consumer. 14 FFDCA§402(f)(1) “In any proceeding under this subparagraph, the
In many respects, passage of the Dietary Supplement Health
and Education Act (DSHEA) in October, 1994, was a safety valve, United States shall bear the burden of proof on each element to show that a
venting consumer discontent with the high degree of restriction placed dietary supplement is adulterated.” 15 FDA has stated that it would use a
upon health claims and the narrowing of the window of avail- ability
of dietary supplements as the result of actions by the FDA. In response “reasonable consumer” standard in determining whether a claim is
to these pressures, a tacit bargain between Congress and the consumers misleading. The reasonable consumer standard replaced the standard of “the
ignorant, the unthinking, and the cred- ulous” consumer, used by courts at the
was struck, whereby Congress granted continued ac- cess by the public
to dietary supplements by (1) providing for this lower threshold of request of FDA in the past (Walsh et al., 2005). 16 Referred in the FFDCA
evidence for safety, (2) changing the role of the FDA from gate-keeper
(§402(f)(1)(A)) as “significant or unreasonable
to policeman (ie, abandoning pre-market approval),14 and (3) allowing
risk of illness or injury.”
a type of claim (ie, structure function claims, not health claims). The
Table 30-14 Uncertainty Parameters and Their Associated Range of Risk Factors
UNCERTAINTY PARAMETERS ESTIMATED RANGE (FACTOR)
Extrapolation model 1–10,000 Total dose vs. dose rate 30–45 Most sensitive sex/strain vs. average sensitivity 1–100 Sensitivity of human vs. test animal 1–100
synergism or antagonism with other carcinogens or promoters 1–1000? Total population vs. target population, potential vs. actual market penetration 1–1000 A
skin, lung) for animals at high dose vs. humans at low dose 1–10 Dose scaling: mg/kg body weight, ppm (diet, water, feed) surface area 1–15 Upper confidenc
exposed 1–10 Specifications or tolerances 1–10 Limits of detection vs. actual levels 1–1000 Additivity vs. nonadditivity of multiple sites 1–3 Survival or interi
adjustments 1–2 Knowledge of only high-end plateau dose response 1–10 Error or variation in detection methods 1–10 Adjustments for less than lifetime bioas
Adjustments for intermittent and less than lifetime human exposure 1–100 Use vs. nonuse of historical data 1–2 Upper confidence and lower confidence limits
in extrapolation level of
acceptable risk
1–1000
Level of acceptable risk 1–1000 Adding or not adding theoretical risks from many substances 1–100
SOURCE: Flamm WG, Lorentzen RJ: Quantitative risk assessment (qra): A special problem in the approval of new products, in Cothern CR, Mehlman MA, Marcus WL
(eds.): Risk Assessment and Risk Management of Industrial and Environmental Chemicals. Princeton Scientific Publishing Co., Inc., Princeton, NJ, 1988.
This interpretation of the Delaney clause was set forth by the FDA in its so-called “constituent policy” published on April 2, 1982, as an Advanced Notice of P
(ANPR). The policy mandates the development and use of animal carcinogenicity data and probabilistic risk assessment to establish a safe level for the contam
under its intended conditions of use.
The constituent policy and, as will be discussed later, the im- plementation of the so-called DES (diethylstilbestrol) proviso for animal drugs under the Delane
the FDA to develop a means for establishing safe levels for carcinogenic substances. The DES proviso allows the addition of carcinogenic animal drugs to anim
no residue in edible tissue as determined by an approved analytic procedure. To do this, the FDA has turned to the use of probabilistic risk assessment in
animals are mathematically extrapolated to an upper bound risk in humans exposed to particular use levels of the additive. The FDA takes the position that c
conservative assumptions inherent in the procedure, an upper bound lifetime risk of one cancer in a million individuals is the biological equivalent of zero.
Much controversy surrounds the use of risk assessment procedures, in part because estimates of risk are highly dependent on the many assumptions that must be
practice of testing at a maximum tolerated dose (MTD) (Williams and Weisburger, 1991) raises the question of appropriateness to human exposure. Do h
physiological changes unlike those from human exposure? The basic assumption in quantitative risk assessment (QRA) that the dose–response curve is linea
observable effect may result in the calculation of relatively high risks even at doses that are much lower than the lowest dose that produces cancer in experim
is more a process than a science; many steps in the process are based on assumptions, not
proven scientific facts. If only the most conservative assumptions are made throughout the process, many will represent overestimates of human risk by 10- or 1
combined overesti- mate of perhaps a million-fold or more. Table 30-14 provides some rough estimates of potential ranges of uncertainty that might lead to
(Flamm and Lorentzen, 1988).
Historically, the FDA has employed a high threshold for establishing that a food or color additive has been found to induce cancer when ingested by human
additives are found to induce cancer, they cannot be approved for foods or colors no matter how small the estimated risk. In the end, very few substances have
banned because of the Delaney clause. Two indirect food additives (Flectol H and mercaptoimidazoline) that migrate from packaging material were banned. Am
safrole, cinnamyl anthranilate, thiourea, and diethylpyrocarbonate were banned because of the Delaney clause, diethylpyrocarbonate because it forms uretha
A number of substances (eg, butylated hydroxyanisole (BHA), xylitol, methylene chloride, sorbitol, trichloroethylene, nitrilotriacetic acid (NTA), diethylhexyl
formaldehyde, bentonite) listed in the Code of Federal Regulation as food additives are also listed as carcinogens by National Toxi- cology Program (NTP), the
for Research on Cancer (IARC), or the state of California (under the Safe Drinking Water and Toxic Enforcement Act of 1986, also known as Propo- sition 65).
and on what basis do these food additive listings continue?
Despite the fact that tests and conditions exist under which each of these substances will produce cancer in animals, the FDA has found it possible to continue lis
as food additives. The reasoning applied in almost every case is based
imbalances. This position allows the agency to argue that changing the
level of protein or fat in the diet does not induce cancer but simply
modulates tumor incidence (Kritschevsky, 1994).
on secondary carcinogenesis. The one exception is formaldehyde,
which is carcinogenic only on inhalation, and there are compelling
reasons to believe that inhalation is not an appropriate test in this case Biological vs. Statistical Significance Much can be learned about the
(Flamm and Frankos, 1985). Therefore, formaldehyde is not treated as proper means of assessing carcinogenicity data by studying large
a carcinogen prohibited by the Delaney clause. databases for substances that have been tested for carcinogenicity many
For BHA, which induces forestomach cancer, the concept times. The artificial sweetener cyclamate is an example. The existence
has been advanced that its carcinogenicity is attributable primarily to a of more than a dozen studies on cyclamate and the testing of multiple
cycle of irritation and restorative hyperplasia (Clayson et al., 1986). hypotheses at dozens of different organ and tissue sites in all these
For xylitol, a sugar alcohol, an increase in bladder tumors and adrenal studies led to the awareness that the overall false-positive error rate
pheochromocytomas is considered secondary to calcium imbalance could be inflated if individual findings were viewed out of context
resulting from the indigestibility of sugar alcohols and their (FDA, 1984). Therefore, very careful attention must be paid to the
fermentation in the lower GI tract. Sorbitol, another sugar alcohol, totality of the evidence.
behaves in a similar manner. For NTA, the argument is secondary The possibility of false–negative error is always of concern
carcinogenesis, and although specific explanations vary, the because of the need to protect public health. However, it should be
mechanism involving zinc imbalance has considerable scientific recognized that any attempt to prove absolutely that a substance is not
support. carcinogenic is futile. Therefore, an unrelenting effort to mini- mize
Thus, the FDA has generally interpreted the phrase “found false-negative errors can produce an unacceptably high probability of
to induce cancer when ingested by man or animals” as excluding a false-positive. Further, demanding certainty (ie, a zero or implicitly
cancers that arise through many secondary means. Therefore, to be a an extremely low probability of false-negative error) has negative
carcinogen under the Delaney clause, a food or color additive must be consequences for an accurate decision-making process. This is the case
demonstrated to induce cancer by primary means when ingested by because it severely limits the ability to discriminate between
humans or animals or to induce cancer by other routes of administration carcinogens and noncarcinogens on the basis of bioassays (FDA,
that are found to be appropriate. This is interpreted to mean that the 1984).
findings of cancer must be clearly reproducible and that the cancers In addition to the false–positive/false–negative trap, which
found are not secondary to nutritional, hormonal, or physiological is a statistical matter, there are many potential biological traps. The test
substance, typically administered at high MTDs, may affect one or response dose-related?); (4) the biological meaningfulness of the effect
more of the many biological processes known to modulate tumor (was it experimentally consistent with the evidence from related studies
incidence at a specific organ site without causing an induction of tu- and did it occur in a target organ?); (5) the reproducibility of the effect
mors at that or any other site. Nutritional imbalances such as choline with other doses, sexes, or species; (6) evidence of hyperplasia,
deficiency are known to lead to a high incidence of liver cancer in rats metaplasia, or other signs of an ongoing carcinogenic process (is the
and mice. Simple milk sugar (lactose) is known to increase the effect supported by a pattern of related non-neoplastic lesions,
incidence of Leydig cell tumors in rats. Caloric intake has been shown particularly at lower doses?); (7) evidence of tumor multiplicity or
to be a significant modifying factor in carcinogenesis. Im- progression; and (8) the strength of the evidence of an increased tumor
pairment of immune surveillance by a specific or nonspecific means incidence (what is the magnitude of the p value, for pairwise
(stress) affecting immune responsiveness and hormonal imbalance can
comparison and for trend?).A good discussion of the use of these
result in higher incidences of tumors at specific organ sites. Hor- monal
imbalance, which can be caused by hormonally active agents (eg, factors by scientists in deciding whether a substance induces cancer
estradiol) or by other substances that act indirectly, such as vitamin D,
in animals is contained in the notice of a final rule permanently listing
may result in an increased tumor incidence. Chronic cell injury and
FD&C Yellow No. 6 (51 Federal Register 41765–41783, 1988). An
restorative hyperplasia resulting from treatment with lemon flavor (D-
elevation of tumor incidence in rats was identified at two organ and/or
limonene) probably are responsible for renal tumor development in
tissue sites: (1) medullary tumors of the adrenal glands in female rats
male rats by mechanisms that are of questionable relevance to humans
only and (2) renal cortical tumors in female rats only. Scientists at the
(Flamm and Lehman-McKeeman, 1991). In these examples, the
FDA concluded that the increase in medullary tumors of the adrenal
increases in tumor incidence at specific organ sites probably are
glands in female rats did not suffice to establish that FD&C Yellow No.
secondary to significant changes in normal physiological balance and
6 is a carcinogen. The basis for the decision was (1) a lack of dose
homeostasis. Moreover, the increases in tumor incidence, and hence
response, (2) the likelihood of false positives, (3) the lack of precan-
the increases in the risk of cancer, probably would not occur except at
cerous lesions, (4) morphological similarity of adrenal medullary
toxic doses (Ames and Gold, 1997).
lesions in treated and control rats, (5) an unaffected latency period, (6)
To preserve the ability of a bioassay to discriminate between a lack of effect in male rats, and (7) a comparison with other studies
carcinogens and noncarcinogens, the possibility of false–positive or in which there was no association between exposure to FD&C Yellow
false–negative results and the possibility of secondary effects must be No. 6 and the occurrence of adrenal medullary tumors.
considered. To be meaningful, evaluations must be based on the weight
A similar judgment was made with respect to the cortical re-
of evidence. Particular attention must be given to the many factors that
nal lesions in female rats, which were not found to provide a basis for
are used in deciding whether tumor incidences are biologically as well
concluding that FD&C Yellow No. 6 can induce cancer of the kidneys.
as statistically significant. These factors include (1) the historical rate
The main reasons leading to this conclusion were (1) the relatively
of the tumor in question (is it a rare tumor, or does it occur frequently
common occurrence of proliferative renal lesions in aged male control
in the controls?); (2) the survival histories of dosed and test animals
rats (28 months or older), (2) the lack of renal tumors in treated males
(did dosed animals survive long enough to be considered “at risk” and
despite their usually greater sensitivity
what effect did chemical toxicity and reduced survival have in the
interpretation of the data?); (3) the patterns of tumor incidence (was the
Carcinogenic Contaminants The Delaney clause, which

prohibits the addition of carcinogens to food, could ban many
to renal carcinogens, (3) the lack of malignant tumors indicating
food additives and color additives if strictly interpreted to
no progression of adenomas to a malignant state, (4) the lack of
include contaminants of additives within its definition. Clearly,
a decreased latency period compared with controls, (5) the
this was not Congress's intent, and just as clearly, the FDA
coinci- dence of renal proliferative lesions and chronic renal
needed to develop a common sense policy for addressing the
disease, (6) the lack of genotoxicity, and (7) a lack of
problem that all substances, including food and color additives,
corroborative evidence from other studies that suggests a
may contain carcinogenic contaminants at some trace level.
treatment-related carcinogenic effect of FD&C Yellow No. 6
on the kidney. Both these examples emphasize the importance Toward this end, the agency argued (FDA, 1982b) that banning
of considering all the evidence in attempting to decide the food and color additives simply because they have been found
significance of any subset of data. or are known to contain a trace level of a known carcinogen
does not make sense because all substances may contain
As essential elements, vitamins, sugars, and calories by them-
carcinogenic contaminants. The agency asserted in its
selves can increase tumor incidence in test animals; the
constituent policy that the mere fact an additive contains a
mechanism by which tumors arise as the result of exposure to
contaminant known to be carcinogenic should not
food or food ingredients is critically important to assessing the
automatically lead the agency to ban that food additive but
relevance of the finding to the safety of the substance under its
should instead cause the agency to consider the health risks it
intended conditions of use in food. McClain (2002) provides an
poses based on its level of contamination and the conditions of
excellent discussion of mechanistic considerations in the
its use (FDA, 1977).
regulation and classification of chemical carcinogens.
SAFETY OF FOOD Adverse Reactions to sensitivity to fish was described in the early 1960s (Frankland,
1987; Taylor et al., 1989; Taylor and Hefle, 2002). This test,
Food or Food Ingredients
which evolved into the (skin) prick test and later the
In a survey of Americans, 30% indicated that they or someone Radioallergosorbent (RAST) test, allowed a distinction to be
in their immediate families has a food sensitivity of one type or made between immunologically based adverse reactions (true
another. Although this number is likely too high, as much as allergies) and adverse reactions with other causation.
7.5% of the population may be allergic (ie, their body's immune
system is activated due to exposure to food ingredient) to some
food or component thereof, such as a peanut allergy (Taylor
et al., 1989). Lactose intolerance (a deficiency of the Food Allergy Description Food hypersensitivity (allergy)
disaccharide enzyme, lactase) is high among some groups; for refers to a reaction involving an immune-mediated response.
example, there is an incidence of 27% in black children age 12– Such a response is generally IgE-mediated, although IgG4-
24 months, which may increase to 33% by age six years
(Juambeltz et al., 1993). The percentage of young northern and cell-mediated immunity also may play a role in some
European children allegedly intolerant to food additives ranges instances (Fukutomiet al., 1994). What generally distinguishes
from 0.03 to 0.23% (Wuthrich, 1993) to 1–2% (Fuglsang et al., food allergy from other reactions is the involvement of
1993). Further, there are certain drug–food incompatibilities immunoglobulins, basophils, or mast cells (the latter being a
about which physicians and pharmacists are obligated to warn source of mediating substances including histamine and
patients, such as monoamine oxidase (MAO) inhibitors and bradykinin for immediate reactions and prostaglandins and
tyramine in cheese or benzodiazapenes and naringenin in leukotrienes for slower-developing reactions) and a need for a
grapefruit juice. People who are prescribed tetracycline also prior exposure to the allergen or a cross-reactive allergen. An
must be alerted not to take milk with this antibiotic. By any allergic reaction may be manifested by one or more of the
standard, there are large numbers of real and perceived symptoms listed in Table 30-16. The list of foods known to
adverse reactions to or incompatibilities with food (Thomas and provoke allergies is long and is probably limited only by what
Cotter, 2002). The first step in understanding people are willing to eat. Although cutaneous reactions and
these reactions is to define the nomenclature, a task undertaken anaphylaxis (ie, severe allergic reaction, resulting in a drop of
by the American Academy of Allergy and Immunology blood pressure, and may be fatal) are the most common
(Committee on Adverse Reactions to Foods) and the National symptoms associated with food allergy, the body is replete
Institute of Allergy and Infectious Diseases (Anderson and with a repertoire of responses that are rarely confined to only a
Sogn, 1984). An adaptation of their definitions and few foods. A curious type of food allergy, the so-called
classification is represented in Table 30-15. In the table, the exercise-induced food allergy, is apparently provoked by
definitions proceed from general to more specific. Obviously, exercise which has been immediately preceded or followed by
there is little to distinguish the terms “adverse reaction” and the ingestion of certain foods (Kivity et al., 1994), including
“sensitivity” to a food or a food “intolerance,” except perhaps shellfish, peach, wheat, celery, and “solid” food (Taylor et al.,
in the lexicon of the individual, colored by his or her own 1989; Taylor and Hefle, 2002). The exact mechanism is
experience. That is, an “adverse reaction” may indicate unknown, but it may involve enhanced mast cell re-
something as simple as an unpleasing esthetic or hedonic sponsiveness to physical stimuli and/or diminished
quality such as an unpleasant taste, which may in fact have a metabolism of histamine similar to red wine allergy (Taylor et
genetic basis as in the ability to taste phenylthiocarbamide al., 1989). Mean- while, food intolerance in patients with
(Guyton, 1971), or may indicate a fatal outcome resulting from chronic fatigue may have less to do with allergic response and
an immune or toxic reaction. has been shown to be a som- atization trait of patients with
Clinical descriptions of adverse reactions to food are not new. depressive symptoms and anxiety disorders (Manu et al.,
Hippocrates (460–370B.C.) first recorded adverse reactions to 1993).
cow's milk that caused gastric upset and urticaria, and Galen
(AD131–210) described allergic symptoms to goat milk. Chemistry of Food Allergens Most allergens (antigens) in
However, the immunologic basis of many adverse reactions food are protein in nature, and although almost all foods
to food was not established until the passive transfer of contain one
Table 30-15 Adverse Reaction to Food: Definition of Terms
TERM DEfiNITION CHARACTERISTICS/EXAMPLES
Adverse reaction (sensitivity) to
a food
General term that can be applied to a clinically
abnormal response attributed to an ingested food or food additive
Any untoward pathological reaction resulting from ingestion of a food or food additive. May be immune-mediated Food hypersensitivity (allergy) An immu
some patients, may occur after only a small amount of the substance is ingested, and is unrelated to any physiological effect of the food or food additive
Immune-mediated (cellular or humoral
response), requires prior exposure to antigen or cross-reacting antigen. First exposure may have been asymptomatic
Food anaphylaxis A classic allergic hypersensitivity reaction to food
or food additives
A humoral immune response most often
involving IgE antibody and release of chemical mediators. Mortality may result Food intolerance A general term de
physiological response to an ingested food or food additive; this reaction may be an immunologic, idiosyncratic, metabolic, pharmacological, or toxic response
Any untoward pathological reaction resulting from ingestion of a food or food additive. May be immune-mediated. Celiac disease (intolerance to wheat, rye, ba
Food toxicity (poisoning) A term use to imply an adverse effect caused by the direct action of a food or food additive on the host recipient without the involvem
mechanisms. This type of reaction may involve nonimmune release of chemical mediators. Toxins may be contained within food or released by microorganism
contaminating food products
Not immune-mediated. May be caused by
bacterial endo- or exotoxin (eg, hemorrhagic E. coli) fungal toxin (eg, aflatoxin), tetrodo-toxin from pufferfish, domoic acid from mollusks, histamine poisonin
(scombroid poisoning), nitrate poisoning (ie, methemoglobinuria)
Food idiosyncrasy A quantitatively abnormal response to a food
substance or additive; this reaction differs from its physiological or pharma-cological effect and resembles hypersensitivity but does not involve immune mecha
idiosyncratic reactions include those which occur in specific groups of individuals who may be genetically predisposed
Not immune-mediated, Favism (hemolytic
anemia related to deficiency of erythrocytic glucose-6-phosphate dehydrogenase), fish odor syndrome, beetanuria, lactose intolerance, fructose, intolerance, asp
wine intolerance
Anaphylactoid reaction to a food An anaphylaxis-like reaction to a food or food additive as a result of nonimmune release of chemical mediators. This reaction
symptoms of food hypersensitivity (allergy)
Not immune-mediated. Scombroid poisoning,
sulfite poisoning, red wine sensitivity
Food–drug interaction A change in the pharmacokinetic or
pharmacodynamic action of a drug as the result of ingestion of a food
Not immune-mediated. Ingestion of fats,
phytates, or fiber to change absorption; upregulation of genes by Brassica, polyunsaturated fats; unregulation of polypeptide transporters by St. Johns wort Me
Toxic effects of a food wh
improperly prepared
Cycasin, vitamin A toxicity, goiterogens,
licorice
SOURCE: Adapted from Anderson JA, Sogn DD (eds.): Adverse Reactions to Foods. Washington, DC, US Department of Health and Human Services, 1984.
or more proteins, a few foods are associated more with allergic reactions than are others. For example, anaphylaxis to peanuts is more common than is anaphyla
(eg, peas, soybeans). Similarly, although allergies may occur from bony fishes, there is no basis for cross-reactivity to other types of seafood (eg, mollus
although dual (and independent) sen- sitivities may exist (Anderson and Sogn, 1984). Interestingly, patients who are allergic to milk usually can tolerate bee
dander, and patients allergic to eggs usually can tolerate ingestion of chicken and feather-derived particles (Anderson and Sogn, 1984), although in the “bird–eg
can
be allergic to bird feathers, egg yolk, egg white, or any combination of the three (DeBlay et al., 1994; Szepfalusi et al., 1994).Some of the allergenic comp
food allergens are listed in Table 30-17. Although food avoidance is usually the best means of protection, it is not always possible because (1) the content of
may be unknown (eg, the presence of eggs or cottonseed oil); (2) there is the possibility of contamination of food from unsuspected sources (eg, Penicillium
Candida albicans (Dayan, 1993; Dorion et al., 1994), and cow's milk antigens in the breast milk of mothers who
Table 30-16 Symptoms of IgE-Mediated Food Allergies
Cutaneous Urticaria (hives), eczema, dermatitis, pruritus, rash Gastrointestinal Nausea, vomiting, diarrhea, abdominal cramps Respiratory Asthma, wheezing, r
bronchospasm Other Anaphylactic shock, hypotension, palatal itching, swelling including
tongue and larynx, methemoglobinemia*
*An unusual manifestation of allergy reported to occur in response to soy or cow milk protein intolerance in infants. SOURCE: Murray KF, Christie, DL: Dietary protein intolerance in infants with transient m
diarrhea. J Pediatr 122:90, 1993, with permission from Elsevier. SOURCE: Adapted from Taylor SL, Scanlan RA (eds.): Food Toxicology: A Perspective on the Relati ve Risks. New York, Marcel Dekker, 19
Copyright Clearance Center.
Table 30-17 Known Allergenic Food Proteins
FOOD ALLERGIC PROTEINS
Cow's milk Casein (Dorion et al., 1994; Stoger and Wuthrich, 1993)
β-Lactoglobulin (Piastra et al., 1994; Stoger and Wuthrich, 1993) a-Lactalbumin (Bernaola et al., 1994; Stoger and Wuthrich, 1993) Egg whites Ovomucoid (
Ovalbumin (Fukotomi et al., 1994; Bernhiesel-Broadbent et al., 1994) Egg yolks Livetin (de Blay et al., 1994; Szepfalusi et al., 1994) Peanuts Ara h II (Dorion
Peanut I (Sachs et al., 1981) Soybeans β-Conglycinin (7S fraction) (Rumsey et al., 1994)
Glycinin (11S fraction) (Rumsey et al., 1994) Gly mIA (Gonzalez et al., 1992) Gly mIB (Gonzalez et al., 1992) Kunitz trypsin inhibitor (Brandon et al., 1
(O'Neil et al., 1993) Shrimp Antigen II (Taylor et al., 1989) Green peas Albumin fraction (Taylor et al., 1989) Rice Glutelin fraction
Globulin fraction (Taylor et al., 1989) Cottonseed Glycoprote in fraction (Taylor et al., 1989) Peach guava, banana, mandarin, strawberry 30 kD protein (Wade
Tomato Several glycoproteins (Taylor et al., 1989) Wheat Gluten (Stewart-Tull and Jones, 1992)
Gliadin (O'Hallaren, 1992) Globulin (O'Hallaren, 1992) Albumin (O'Hallaren, 1992) Okra Fraction I
SOURCE: Modified from Taylor SL, Scanlan RA (eds.): Food Toxicology: A Perspective on the Relative Risks. New York, Marcel Dekker, 1989, p. 265.
With permission from Copyright Clearance Center.
only 1–2% of
young children (4–15 years) susceptible (Fuglsanget al., 1993).
have consumed cow's milk (Halken et al., 1993)); (3) the pres- The increase in the number of adults exhibiting food allergy
ence of an allergen in a previously unknown place (the insertion may be due in part to an expanded food universe, that is, an
of Brazil nut DNA into soybeans and subsequent appearance of increased willingness to try different foods. In one study,
the allergic 2S protein in soybean products (Nordlee et al., allergies among young children were most commonly to milk
1996)); and (4) there is a lack of knowledge about the and eggs, whereas allergies that developed later in life tended
phylogenetic relationships between food sources (legumes to be to fruit and vegetables (Kivity et al., 1994).Familial
include peas, soybeans, and peanuts).
relationships also play a role. Schrander and col- leagues
Demographics of Food Allergy and Intolerance Although (1993) noted that among infants with cow's milk protein
children appear to be the most susceptible to food allergy, with intolerance, 65% had a positive family history (first- or second-
adverse reactions occurring in 4–6% of infants, the incidence degree relatives) for atopy compared with 35% of healthy
appears to taper off with maturation of the digestive tract, with controls.
Table 30-18 Idiosyncratic Reactions to Foods
FOOD REACTION MECHANISM REFERENCE
Fava beans Hemolysis, sometimes accompanied by
jaundice and hemoglobinuria; also, pallor, fatigue, nausea, dyspnea, fever and chills, abdominal and dorsal pain
Pyramidene aglycones in fava bean
cause irreversible oxidation of GSH in G-6-PD-deficient erythrocytes by blocking NADPH supply, resulting in oxidative stress of the erythrocyte and eventual
Chevion et al., 1985
Chocolate Migraine headache Phenylethylamine-related (?) Gibb et al., 1991; Settipane, 1987 Beets Beetanuria:
(often mistaken for hematuria)
Excretion of beetanin in urine after
consumption of beets
Smith, 1991
Asparagus Odorous, sulfurous-smelling urine Autosomal dominant inability to
metabolize methanthiol of asparagus and consequent passage of methanthiol in urine
Smith, 1991
Red Wine Sneezing, flush, headache, diarrhea,
skin itch, shortness of breath
Diminished histamine degradation: deficiency of diamine oxidase (?) Histamines present in wine
Wantke et al., 1994
Choline- and carnitine-
containing foods
Fish odor syndrome: foul odor of body
secretions
Choline and carnitine metabolized to
trimethylamine in gut by bacteria, followed by absorption but inability to metabolize to odorless trimethylamine N-oxide
Ayesh et al., 1993
Milk Abdominal pain, bloating, diarrhea Lactase deficiency Mallinson, 1987 Fructose-containing
foods
Abdominal pain, vomiting, diarrhea,
hypoglycemia
Reduced activity of hepatic aldolase B
toward fructose-1-phos phate
Frankland, 1987;
Catto-Smith and Adams, 1993
Food Toxicity (Poisoning) See “Substances for which tolerances may not be set.”
Food Idiosyncrasy Food idiosyncrasies are generally defined as quantitatively abnormal responses to a food substance or additive; this reaction differs from the
and although it may resemble hypersensitivity, it does not involve immune mechanisms. Food idiosyncratic reactions include those that occur in specific group
may be genetically predisposed. Examples of such reactions and the foods that probably are responsible are given in Table 30-18.
Probably the most common idiosyncratic reaction is lactose intolerance, a deficiency of the lactase enzyme needed for the metabolism of the lactose in cow's
enzyme results in fermentation of lactose to lactic acid and an osmotic effect in the bowel, with resultant symptoms of malabsorption and diarrhea. Lactose in
northern Europe at 3– 8% of the population; it reaches 70% in southern Italy and Turkey and nearly 100% in southeast Asia (Anderson and Sogn, 1984; Gudm
Anaphylactoid Reactions Anaphylactoid reactions are historically thought of as reactions mimicking anaphylaxis through direct application of the primary med
reactions: histamine. Ingestion of scombroid fish (eg, tuna, mackerel, bonito) as well as some nonscombroid fish (mahimahi and bluefish) that have
microorganisms to produce histamine may
result in an anaphylactoid reaction also called “scombrotoxicosis” (Table 30-19) (Clark et al., 1999). The condition was reported to be mimicked by the direct i
histamine in un- spoiled fish (Van Geldern et al., 1992), but according to Taylor (1986), the effect of simply ingesting histamine does not produce the equiv
Taylor claims that histamine ingested with spoiled fish appears to be much more toxic than is histamine ingested in an aqueous solution as a result of the pre
potentiators in fish flesh. The apparent mechanism of poten- tiation involves the inhibition of intestinal histamine-metabolizing enzymes (diamine oxidase), wh
histamine uptake. Melnik et al. (1997) proposed that anaphylactoid responses may be the sum of several mechanisms: (1) an increased intake of biogen
histamine) with food, (2) an increased synthesis by the intestinal flora, (3) a diminished catabolism of bio- genic amines by the intestinal mucosa, and (4) an i
endogenous histamine from mast cells and basophils by histamine-releasing food. Scombrotoxicosis in the absence of high histamine levels (less than the FDA
of 50 mg histamine/100 g fish) was reported by Gessner et al., 1996. Ijomah et al. (1991) claimed that dietary histamine is not a major determinant of scomb
potency is not positively correlated with the dose and volunteers tend to fall into susceptible and nonsusceptible subgroups. Ijomah et al. (1991) suggested that e
released by mast cells plays a significant role in the etiology of scombrotoxicosis, whereas the role of dietary histamine is minor. An exception to this end
theory was described by Morrowet al. (1991), who found the
Table 30-19 Anaphylactoid Reactions to Food

Facial flushing, headache Histamine poisoning; histamine
Western Australian concentration in plasma correlated closely with histamine dose
salmon (Arripis truttaceus) ingested
Erythema and urticaria of the skin, Van Gelderen et al.,
facial flushing and sweating, palpitations, hot flushes of the Van Gelderen et al.,
body, headache, nausea, vomiting, and dizziness 1992
Scombroid poisoning; high histamine 1992
Scombroid poisoning; high histamine
levels demonstrated in the fish Cape yellow tail (fish) (Seriola lalandii)
levels demonstrated in the fish Skin rash, diarrhea, palpitations,
Smart, 1992 headache, nausea and abdominal cramps, paraesthesia,
Smart, 1992 unusual taste sensation, and breathing difficulties
Smart, 1992 Scombroid poisoning, treated with
Scombroid poisoning, treated with
antihistamines.
antihistamines.
Muller et al., 1992
Fish (spiked with Muller et al., 1992
histamine) Muller et al., 1992
Sulfite sensitivity Bronchospasm, asthma Sulfite oxidase of food and drug interactions are actually the result of food-
deficiency to induced changes in drug bioavailability or metabolism (ie,
meta-bisulfites in foods and wine pharmacokinetic interactions), although some are the result of
Smith, 1991 pharmacodynamic interactions. For drugs with a narrow
therapeutic index and the need for dose titration, even small
Tuna, albacore, changes in the dose–response effects can have great
consequences (Schmidt and Dalhoff, 2002). The potential to
mackerel, bonito, mahimahi, and bluefish
alter therapeutic effect can be great and in recognition of the
Reaction resembling an acute allergic
role that food plays, test meals are now given to determine their
reaction effect on drug therapeutic effect (FDA, 2002b).
Scombroid poisoning treated with antihistamines and
Pharmacokinetic effects on absorption (eg, gastric pH, gastric
cimetidine
emptying, lymphatic flow) were described earlier. Examples of
foods affecting a number of cytochromes, Phase II enzymes,
cimetidine
and transporters are provided in Table 30-20, although the
effects on CYP3A4 and P-glycoprotein may be the clinically
cimetidine
most important (Harris et al., 2003). Other dietary ingredients
that may produce an
cimetidine
effect on the overall pharmacokinetics of drugs would include
Lange, 1988
substances that would change the pH of urine or simply the
Lange, 1988
presence of fiber in the intestine. Examples of
Lange, 1988
pharmacodynamic interactions might include the effect of
unsaturated fatty acids in the diet on anti- coagulants or
membrane potentials of the membranes in which they become
incorporated; or high potassium intake from potassium-rich
Cheese Symptoms resembling acute allergic
foods and the risk of hyperkalemia during therapy with
reaction angiotensin enzyme converting enzyme inhibitors or
Responds to antihistamines; histamine spironolactone (Schmidt and Dalholf, 2002). Other
poisoning? pharmacodynamic interactions might include phytoestrogens
Taylor, 1986 and other estrogen-stimulating substances during treatment for
Taylor, 1986 hormonally sensitive cancers (eg, breast and prostate) and;
caffeine or other stimulatory methylxanthines from coffee,
chocolate, and soft drinks flavored with guarana, during treat-
ment for hypertension.
expected increase in urinary histamine in scombroid-poisoned
individuals but did not find an increase in urinary 9α,11β-
dihydroxy- 15-oxo-2,3,18,19-tetranorprost-5-ene-1,20-dioic
Metabolic Food Reactions Metabolic food reactions are
acid, the principal metabolite of prostaglandin D2, a mast cell distinct from other categories of adverse reactions in that the
foods are more or less commonly eaten and demonstrate toxic
secretory product; thus, no mast cell involvement was effects only when eaten to excess or improperly processed
indicated. (Table 30-21). The susceptible population exists as a result of
Smith (1991) described sulfite-induced bronchospasm (some- its own behavior, that is, the “voluntary” consumption of food
times leading to asthma), which was first noticed as an acute as a result of a limited food supply or an abnormal craving for
sensitivity to meta-bisulfites sprayed on restaurant salads and a specific food. Such an abnormal craving was reported by
in wine. Sulfite normally is detoxicated rapidly to inorganic Bannister et al. (1977), who noted hypokalemia leading to
sulfate by the enzyme sulfite oxidase. In sensitive individuals, cardiac arrest in a 58-year-old woman who had been eating
there is apparently a deficiency in this enzyme, making them about 1.8 kg of licorice per week. In “glycyrrhizism,” or licorice
supersensitive to sulfites. Thus, the addition of sulfite to food is intoxication, glycyrrhizic acid is the active component, with an
considered safe only when properly disclosed on the food label. effect resembling that of aldosterone, which suppresses the
renin–angiotensin–aldosterone axis, resulting in the loss of
potassium. Clinically, hypokalemia with alkalosis, cardiac
Food–Drug Interactions Once known as pharmacological arrhythmias, muscular symptoms together with sodium
food reactions or as “false food allergies” (Moneret-Vautrin, retention and edema, and severe hypertension are observed. The
1987), these adverse reactions were once thought to be syndrome may develop at a level of 100 g licorice/day but
exaggerated responses to pharmacological agents in food and gradually abates upon withdrawal of the licorice (Isbrucker and
possibly due to receptor sen- sitization. However, the majority Burdock, 2006).
Table 30-20 Food–Drug Interactions (Activity may be Enhanced or Inhibited)
ENZYME OR TRANSPORTER FOOD DRUG
CYP1A2 Caffeine, theophylline, grapefruit juice (naringen and
furanocoumarins bergamottin and dihydroxybergamotin), grape juice, cruciferous vegetables, apiaceous vegetables, cooked meat
Clozapine, fluvoxamine, imipramine
CYP2E1 Watercress and possibly other
isothiocyanate-containing cruciferous vegetables; polyunsaturated fatty acids (corn oil, menhaden oil)
Ethanol, halothane, enflurane
CYP3A4 Grapefruit juice, orange juice, red wine, possibly
other polyphenol-containing substances, St. Johns wort, garlic
Ketoconazole, cyclosporin, erythromycin, protease
inhibitors, HMG-CoA reductase inhibitors
UGT &GST Brussel sprouts, cabbage, watercress, broccoli Acetominophen, oxazepam, morphine, ibuprofen P-glycopeptide &OATP
Vegetables, fruit juice, St. Johns wort Digoxin, cyclosporine, pravastatin
UGT, uridine diphosphate glycuronosyltransferases; GST, glutathione-S-transferases; OATP, organic anion transporting polypeptides.
Table 30-21 Metabolic Food Reactions
Lima beans, Cassava roots, millet (sorghum) sprouts, bitter almonds, apricot, and peach pits
Cyanosis Cyanogenic glycosides releasing
hydrogen cyanide on contact with stomach acid
Anderson and Sogn, 1984
Cabbage family, turnips, soybeans, radishes, rapeseed, and mustard
Goiter (enlarged thyroid) Isothiocyanates, goitrin, or
S-5-vinly-thiooxazolidone interferes with utilization of iodine
Anderson and Sogn, 1984; van Etten and Tookey, 1985 Unrip
tree Blighia sapida, common in Caribbean and Nigeria
Severe vomiting, coma, and acute
hypoglycemia sometimes resulting in death, especially among the malnourished
Hypoglycin A, isolated from the fruit,
may interfere with oxidation of fatty acids, so that glycogen stores have to be metabolized for energy, with depletion of carbohydrates, resulting in hypoglycem
Evans, 1985
Leguminosae, Cruciferae Lathyritic symptoms: neurological
symptoms of weakness, leg paralysis, and sometimes death
L-2-4-Diaminobutyric acid inhibition of
ornithine transcarbamylase of the urea cycle, inducing ammonia toxicity
Evans, 1985
Licorice (glycyrrhizic acid) Hypertension, cardiac enlargement,
sodium retention
Glycyrrhizic acid mimicking
Mineralocorticoids.
Farese et al.,
1991 Polar bear and Chicken liver Irritability, vomiting, increased
intracranial pressure, death
Vitamin A toxicity Bryan, 1984
Cycads (cycad flour) Amyotrophic lateral sclerosis (humans),
hepatocarcinogenicity (rats and nonhuman primates)
Cycasin (methylazoxymethanol);
primary action is methylation, resulting in a broad range of effects from membrane destruction to inactivation of enzyme systems
Matsumoto,
1985; Sieber et al., 1980
Isothiocyanates are present in a number of foods, especially cruciferous vegetables; in mustard and horseradish (as allyl isothiocyanate), providing the 'bite' a
foods and in watercress (as methyl isothiocyanate), which confers a slight zaniness to the taste. In mustard seed, the glycoside, sinigrin, is acted upon by my
of water and when the seed is injured, liberating the (allyl)-isothiocyanate, a potent antimicrobial (espe-
cially antifungal). Other members of the Brassica family, including broccoli, kale, and cabbage, release thiocyanate ion. Once ingested, both the iso- and thio
in the body, preventing its organification, leading to diffuse hyperplastic (iodine-deficient) goiter. Although the degree to which I− is bound by the thiocyana
), nev
in areas of low iodine to say, and percholorate high Brassica anion consumption, (ClO−4
nausea, vomiting, abdominal cramps, and/or diarrhea within
hours. Those consuming ferns subjected to more rigorous
processing (eg, boiling for at least 6 minutes) did not experience
could result (Capen et al., 2002; Farwell and Braverman, 2006). symptoms. The authors speculated the ferns contained a heat-
Ermans et al. (1972) indicate that chronic consumption of thio- labile toxin and recommended that ferns be boiled for 10
cyanate may play a role in endemic cretinism. Paradoxically, minutes prior to eating (MMWR, 1994).
excess iodine may also cause goiter (ie, iodine-excess goiter).
Excess iodine appears primarily to block the release of T3 and Importance of Labeling
−
T4 from thy- roglobulin and interferes with peroxidation of 2I The importance of labeling was first realized in its ability to
to I2 and disrupts the conversion of monoiodothyronine to protect consumers from economic fraud by requiring that the
weight and
diiodothyronine (Capen et al., 2002). The FDA is aware of the
possibility of iodine toxicity and has placed limits on iodine in
kelp, the products of which have extensive use in food.17
17 21CFR §172.365.
exact contents of the product be stated; otherwise, the product
This category also includes the ingestion of improperly pre-
was mislabeled. Later, it became obvious that labels could also
pared food such as cassava or cycad, which if prepared properly
serve a purpose in assuring the safety of the consumer by
will result in a toxin-free food. Exposure to cycad seed kernel
including safety warnings for particularly susceptible groups.
is an etiologic factor for the westernPacific amyotrophic lateral
sclerosis (ALS) and parkinsonism-dementiacomplex (PDC); Food allergies have a considerable impact on modern society.
present also are mutagenic and carcinogenic substances. The There is no known cure for food allergies and although
neurotoxins found in cycad are beta-N-methylamino-L-alanine accidental exposure is common, avoidance of the offending
(BMAA)and methylazoxymethanol beta-D-glucoside foods is the only successful noninterventional approach. Food
(cycasin). Cyanogenic glycosides are also found in cassava (as allergy is the leading cause of anaphylaxis, a severe type of
they are in lima beans). The cycad (Ca- caos circinalis) is a allergic reaction requiring hospitalization. It is estimated that
particularly hardy tree in tropical to subtropical habitats around 2% of adults and about 5% of infants and young children in the
the world. Cycads often survive when other crops have been United States suffer from food allergies. Approximately
destroyed (eg, a natural disaster such as a typhoon or drought) 30,000 individuals require emergency room treatment, 2000 are
and therefore may serve as an alternative source of food. hospitalized, and 150 die because of allergic reactions to food.18
Among people who have used cycads for food, the method of Effective January 1, 2006, as a result of the Food Allergen
detox- ification is remarkably similar despite the wide range of Labeling and Consumer Protection Act of 2004 (FALCPA),
this plant: The seeds and stems are cut into small pieces and manufacturers are required to identify the presence of
soaked in water for several days and then are dried and ground ingredients that contain protein derived from milk, eggs, fish,
into flour. The effec- tiveness of leaching the toxin (cycasin) crustacean shellfish, tree nuts, peanuts, wheat, or soybeans.
from the bits of flesh is most directly dependent on the size of These eight major food allergens account for 90% of food
the pieces, the duration of soaking, and the number of water allergic reactions. In addition, FAL- CPA labeling regulations
changes (Matsumoto, 1985). Shortcuts in processing may have require declaration of the specific type of tree nut (eg, almonds,
grave consequences. pecans, or walnuts), the species of fish (eg, bass, flounder, or
Fiddleheads (crosiers) of the ostrich fern (Matteuccia cod), and the kind of crustacean shellfish (eg, crab, lobster, or
struthiopteris) are a seasonal delicacy harvested commercially shrimp). FALCPA requires with a few exceptions the label on
in the northeastern United States and in coastal provinces of a food product (conventional foods, dietary supplements, infant
Canada. The ostrich fern was a spring vegetable for American formula, and medical foods) that is or contains an ingredient
Indians of eastern North America and became part of the (spice, flavoring, coloring, or incidental additive) that includes
regular diet of set- tlers to New Brunswick in the late 1700s. a “major food allergen” (Carabin and Magnuson, 2006).
Until recently, it was consumed primarily in the Maritime Labeling requirements for nonallergens include those for in-
Provinces of Canada and in the northeastern United States. The tolerance (eg, lactose or gluten intolerance) or the presence of
ferns are available commercially either canned or frozen, but phenylalanine for PKU patients, are especially important when
since the early 1980s, farmers' mar- kets and supermarket these substances may be present in foods where their presence
chains have sold fresh ferns in season. None of the fiddlehead may not be expected. Label warnings also include those
ferns of eastern and central North America previously have warning of a threshold for a laxative effect (eg, polydextrose,
been reported to be poisonous. Although some ferns may be mannitol, sorbitol). The FDA has indicated that, at this time,
carcinogenic, the ostrich fern has been considered to be safe to they are not aware of any information that foods developed
eat either raw or cooked. However, in May 1994, outbreaks of through genetic engineering differ as a class in any attribute
food poisoning were associated with eating raw or lightly from foods developed through conventional means that would
cooked fiddlehead ferns in New York and western Canada. warrant a special label (Thompson, 2000). The FDA allows
Approximately 60% of restaurant patrons consuming raw or companies to include on the label of a product any statement as
minimally processed ferns (eg, light saut ́e ing) experienced long as the statement is truthful and not misleading.
TOLERANCE SETTING FOR SUBSTANCES pesticides. It is illegal to use a pesticide unless it is specifically
registered and labeled for the intended use. In order to obtain
IN FOODS Pesticide Residues
registration, an applicant must supply EPA with data on
A pesticide is defined under the Federal Insecticide, Fungicide pesticide composition, mammalian and ecological toxicity,
and Rodenticide Act (FIFRA), as any substance used to control environmental fate, and potential human and environmental
or mit- igate pests (such as insects, rodents, weeds, or fungi), or exposures.
intended for use as a plant growth regulator, defoliant, or
dessicant. In the United States, the regulation of pesticides is
the responsibility of the Environmental Protection Agency 18 http://www.cfsan.fda.gov/∼dms/alrgact.html (site visited 8
(EPA) and is accomplished under both FIFRA and the FD&C

April 2006).
Act. FIFRA governs the registration, sale, and use of all
drug residues in human food. Determination of the potential human
health hazards associated with animal drug residues is complicated by
the metabolism of an animal drug, which results in residues of many
A major part of the registration process for most pesticides potential metabolites.
involves the establishment of tolerances. The EPA must establish The primary factors which must be considered in the
tolerances, or exemptions from tolerances, for all pesticides that may evaluation of animal drugs are (1) consumption and absorption by the
come into contact with food or feed, ie, those intended for use during target animal, (2) metabolism of the drug by the target food animal, (3)
the production, storage, transportation, or processing of food or feed excretion and tissue distribution of the drug and its metabolites in food
crops, on livestock, or in food-handling establishments. The tolerances animal products and tissues, (4) consumption of food animal products
are intended to represent the highest expected residue levels from legal and tissues by humans, (5) potential absorption of the drug and its
uses of the pesticide. All pesticide tolerances are now established under metabolites by humans, (6) potential metabolism of the drug and its
Section 408 of the FD&C Act. Prior to 1996, if pesticide residues in metabolites by humans, and (7) potential excretion and tissue
processed foods exceeded those in raw agricultural commodities, they distribution in humans of the drug, its metabolites, and the secondary
were considered to be intentional food additives and were required to human metabolites derived from the drug and its metabolites. Thus, the
be assigned “Food Additive Toler- ances” under Section 409 of the Act. pharmacokinetic and biotransformation characteristics of both the
If the pesticide chemical in question had been classified by the EPA as animal and the human must be considered in an assessment of the
a human or animal carcinogen, the Delaney clause would be invoked potential human health hazard of an animal drug.
and the Section 409 food additive tolerance(s) could be denied on that When an animal drug is considered GRAS, the safety assess-
basis. However, the Food Quality Protection Act (FQPA) of 1996 ment of the drug is handled as described under the section on GRAS.
revised Section 201(s) of the FD&C Act to exclude pesticides from the With respect to new animal drugs, safety assessment is concerned
definition of food additive—even in the case of concentration residues primarily with residues that occur in animal food products (milk,
in processed fractions. Although an additional tolerance for a cheese, etc.) and edible tissues (muscle, liver, etc.). Toxicity studies in
processed fraction is still required if the pesticide residue in the fraction the target species (chicken, cow, pig, etc.) should provide data on
exceeds the tolerance for the raw agricultural commodity (RAC), that metabolism and the nature of metabolites, along with data on the drug's
tolerance is now established under Section 408 rather than Sec- tion pharmacokinetics. During this phase, the parent drug and its
409. Consequently, although the Delaney clause has not been repealed metabolites are evaluated both qualitatively and quantitatively in the
from Section 409, and continues to apply to intentional food additives animal products of concern (eggs, milk, meat, etc.). This may involve
other than pesticides, it is no longer applicable for pesticides. the development of sophisticated analytic methodologies. Once these
Prior to 1996, the EPA used 100× as a default safety factor data are obtained, it is necessary to undertake an assessment to
when conducting risk assessments to ensure that the necessary food and determine potential human exposure to these compounds from the diet
feed tolerances would be safe for human health. However, FQPA also and other sources, pursuant to the establishment of a tolerance.
requires that an additional 10× safety factor “shall be applied for To comply with the Congressional intent regarding the use of
infants and children to take into account potential pre- and postnatal animal drugs in food-producing animals as required in the no residue
toxicity and completeness of the data with respect to exposure and provision of the Delaney clause, the FDA began to build a system for
toxicity to infants and children.” It further states, however, that “the conducting risk assessment of carcinogens in the early 1970s (FDA,
Administrator may use a different margin of safety for the pesticide 1977). In the course of developing a policy and/or regulatory defi-
chemical residue only if, on the basis of reliable data, such margin will nition for “no residue,” the FDA was compelled to address the issue of
be safe for infants and children.” residues of metabolites of animal drugs known to induce cancer in
humans or animals. As the number of metabolites may range into the
Drugs Used in Food-Producing Animals hundreds, it became apparent that as a practical matter, not every
metabolite could be tested with the same thoroughness as the parent
An animal drug “means any drug intended for use for animals other animal drug. This forced the FDA to consider threshold assessment for
than man” [section 201(w) of the FD&C Act]. Animal drugs, which the first time. Threshold assessment combines information on the
typically are used for growth promotion and increased food produc- structure and in vitro biological activity of a metabolite for the purpose
tion, present a complex problem in the safety assessment of animal of determining whether carcinogenicity testing is necessary (Flamm et
al., 1994, 2002). If testing is necessary and if the substance is found marine origin, contain unavoidable contaminants at some level.
to induce cancer, the FDA's definition states that a lifetime risk of one Tolerances for residues of unavoidable contaminants are established
in a million is equivalent to the meaning of “no residue” as intended by for foods and food ingredients to ensure that they are safe under ex-
Congress. pected or intended conditions of use.
Unavoidable Contamination during Growth, Heavy Metals There are 92 natural elements; approximately 22 are
Storage, or Processing known to be essential nutrients of the mammalian body and are referred
to as micronutrients (Concon, 1988). Among the micronutrients are
Certain substances, such as polyhalogenated aromatic hydrocarbons iron, zinc, copper, manganese, molybdenum, selenium, iodine, cobalt,
(PHAHs), including dioxins, dibenzofurans, and biphenyls, or heavy and even aluminum and arsenic. However, among the 92 elements,
metals, are unavoidable in food because of their widespread use, lead, mercury, and cadmium are familiar as contaminants or at least
presence in the earth's crust which has resulted in their becoming a have more specifications setting their limits in food ingredients (eg,
persistent and/or ubiquitous contaminant in the environment or Food Chemicals Codex (FCC, 2003)). The prevalence of these
presence as a product of normal food processing. As a result, foods and elements as contaminants is due to their ubiquity in nature but also to
animal feeds, principally those of animal (eg, PHAHs accumulate in their use by humans.
dairy/meat products due to lipophilicity of these compounds) and
ceramic ware glazes, have resulted in a steady decline in dietary
lead intake. Although food and water still contribute lead to the
diet, data from the FDA's Total Diet Study indicated a reduction
Lead Although the toxicity of lead is well known, lead may be in mean dietary lead intake for adult males from 95 μg/d in 1978
an essential trace mineral. A lead deficiency induced by feeding to 9 μg/d in the period 1986–1988 (Shank and Carson, 1992).
rats <50 ppb (vs. 1000 ppb in controls) over one or more gener- Some lead sources are difficult to curtail as lead often survives
ations, produced effects on the hematopoietic system, food processing; for example, lead in wheat remains in the
decreased iron stores in the liver and spleen, and caused finished flour (Linder, 1991). Therefore, reducing the
decreased growth (Kirchgessner and Reichmayer-Lais, 1981), contribution from dietary sources remains a challenge, but
but apparently not as a result of an effect on iron absorption. elimination of lead-soldered cans, lead-soldered plumbing, and
Although the toxic effects of lead are discussed elsewhere in especially the use of tetraethyl lead as a gasoline additive has
this text, it is important to note that the effects are profound produced substantial reductions in lead ingestion. What is
(especially in children) and appear to be long-lasting, because needed now is continued vigilance of largely imported lead-
mechanisms for excretion appear to be inadequate in based ceramic ware, lead-containing calcium supplements,
comparison to those for uptake (Linder, 1991). Foods may and lead leaching into groundwater (Shank and Carson, 1992).
become contaminated with lead if they are grown, stored, or
processed under conditions that could introduce larger amounts
Arsenic Arsenic is a ubiquitous element in the environment; it
of lead into the food, such as when a root crop is grown in soil
ranks 20th in relative abundance among the elements of the
that has been contaminated from the past use of leaded
earth's crust and twelfth in the human body (Concon, 1988).
pesticides. Under such conditions, the resulting contamination
(Because arsenic is discussed in detail elsewhere in this text,
of the food may pose a health risk to consumers.
the discussion here is limited to its relationship to foods.) There
Over the years, recognition of the serious nature of lead poison- is some competition for arsenic absorption with selenium,
ing in children has caused the World Health Organization which is known to reduce arsenic toxicity; arsenic is also known
(WHO) and FDA to adjust the recommended tolerable total to antagonize iodine metabolism and inhibit various metabolic
lead intake from all sources of not more than 100 μg/d for processes, as a result affecting a number of organ systems.
infants up to 6 months old and not more than 150 μg/d for There are a number of sources of arsenic, including drinking
children from 6 months to 2 years of age to the considerably water, air, and pesticides (Newberne, 1987), but arsenic
lower range of 6–18 μg/d as a provisional tolerable range for consumed via food is largely in proportion to the amount of
lead intake in a 10-kg child. As the result of recent publicity, seafood
the FDA is recommending that lead levels in candy products eaten (74% of the arsenic in a market-basket survey came from
likely to be consumed frequently by small children not exceed the meat-poultry-fish group, of which seafood has the
0.1 ppm because such levels are achievable under good consistently highest concentration) (Johnson et al., 1981).
manufacturing practices and would not pose a significant risk Although arsenic is used as an animal feed additive, this source
to small children for adverse effects. This recommended does not contribute much to the body burden, as 0.1% arsanilic
maximum level is consistent with the FDA's longstanding goal acid or docecylamine- p-chlorophenylarsonate fed to turkeys
of reducing lead levels in the food supply (FDA, 2005). resulted in tissue residues of only 0.31 and 0.24 ppm in fresh
Initiatives to reduce the level of lead in foods, such as the move muscle (Underwood, 1973).
to eliminate lead-soldered seams in soldered food cans that was At a time when arsenic use was common as a pesticide, acute
begun in the 1970s, and efforts to eliminate leachable lead from poisoning with arsenic often resulted from mistaking arsenic for
sugar or baking soda and adding it to food. The time between two historical incidents of cadmium poisoning, one involved
exposure and symptoms ranged from 10 minutes to several the use of cadmium- plated containers to hold acidic fruit
days, and the symptoms include burning of the mouth or throat, slushes before freezing. Up to 13–15 ppm cadmium was found
a metallic taste, vomiting, diarrhea (watery and bloody), in the frozen confection, 300 ppm in lemonade, and 450 in
borborigmi (rumbling of the bowels caused by movement of raspberry gelatin. Several deaths resulted. A more recent
gas in the GI tract), painful tenes- mus (spasm of the anal or incident of a chronic poisoning involved the dumping of mining
vesical sphincter), hematuria, dehydration, jaundice, oliguria, wastes into rice paddies in Japan. Middle-aged women who
collapse, and shock. Headache, vertigo, muscle spasm, stupor, were deficient in calcium and had had multiple pregnancies
and delirium may occur (Bryan, 1984). Episodes of acute seemed to be the most susceptible. Symptoms included
arsenic poisoning are now rare. hypercal- ciuria; extreme bone pain from osteomalacia;
lumbago; pain in the back, shoulders, and joints; a waddling
Cadmium Cadmium is a relatively rare commodity in nature gait; frequent fractures; pro- teinuria; and glycosuria. The
and usually is associated with shale and sedimentary deposits. disease was called itai itai (ouch-ouch disease) as a result of the
It is often found in association with zinc ores and in lesser pain with walking. The victims had a reported intake of 1000
amounts in fossil fuel. Although rare in nature, it is a nearly μg/d, approximately 200 times the normal intake in unexposed
ubiquitous element in American society because of its populations (Yamagata and Shigematsu, 1970). Cadmium
industrial uses in plating, paint pigments, plastics, and textiles. exposure has also been associated with cancer of the breast,
Exposure to humans often occurs through secondary routes as lung, large intestine, and urinary bladder (Newberne, 1987).
a result of dumping at smelters and refining plants,
disintegration of automobile tires (which contain cadmium-
laden rubber), subsequent seepage into the soil and Chlorinated Organics Chlorinated organics have been with us
groundwater, and inhalation of combustion of cadmium- for some time, and given their stability in water and resistance
containing materials. The estimated yearly release of cadmium to oxidation, ultraviolet light, microbial degradation, and other
from automobile tires ranges from 5.2 to 6.0 metric tons sources of natural destruction, chlorinated organics will
(Davis, 1970; Lagerwerff and Specht, 1971). continue to reside in the environment for some time to come,
Although like mercury, cadmium can form alkyl compounds, albeit in minute amounts. However, with the introduction of
unlike mercury, the alkyl derivatives are relatively unstable and chlorinated hydrocarbons as pesticides in the 1930s, diseases
consumption almost always involves the inorganic salt. Of associated with an insect vector such
Table 30-22 Examples of Levels of Chlorinated Hydrocarbons in British Food
CHLORINATED HYDROCARBONS μg/kg
FOOD CHCl3 CCI4 TCE TCEY TTCE PCE HCB HCBD PerCE
Milk 5.0 0.2 0.3 — — 1.0 0.08 0.3 Cheese 33.0 5.0 3.0 0.0 0.0 0.0 0.0 2.0 Butter 22.0 14.0 10.0 — — — 2.0 13.0 Chicken eggs 1.4 0.5 0.6
0.0 0.0 0.0 0.0 0.0 Beef steak 4.0 7.0 3.0 16.0 0.0 0.0 0.0 0.0 0.9 Beef fat 3.0 8.0 6.0 12.0 1.0 Pork liver 1.0 9.0 4.0 22.0 0.5 0.4 5.0 Margarine
3.0 6.0 — 0.8 7.0 Tomatoes 2.0 4.5 — 1.7 1.0 70.1 0.8 1.2 Bread (fresh) 2.0 5.0 2.0 7.0 — — — — 1.0 Fruit drink (canned) 2.0 0.5 — 5.0
0.8 2.0
CHCI3, chloroform; CCI4, carbon tetrachloride; TCE, trichloroethane; TCEY, trichloroethylene; TTCE, tetrachloroethane;
PCE, pentachloroethane; HCB, hexachlorobenzene; HCBD, hexachlorobutadiene; PerCE, perchloroethylene. SOURCE: Modified from McConnell, G. Gerguson, GM Pearson CR:
Chlorinated hydrocarbons and the environment.
Endeavour 34:14, 1975, with kind permission from Elsevier Science.
described a method for interpreting the differing potencies of carcino-
gens and human exposures: the percentage HERP (human exposure
as malaria were nearly eliminated. In the industrialized world, chlo- dose/rodent potency dose). Using this method, they demonstrated that
rinated organics brought the promise of nearly universal solvents, and the hazard from trichloroethylene-contaminated water in Sil- icon
their extraordinary resistance to degradation made them suit- able for Valley or Woburn, Massachusetts, or the daily dietary intake from
use as heat transfer agents, carbonless copy paper, and fire retardants DDT (or its product, DDE) at a HERP of 0.0003–0.004% is
(Table 30-22). considerably less than the hazard presented by the consumption of
As persistent as these substances are in the environment and symphytine in a single cup of comfrey herb tea (0.03%) or the hazard
despite the degree of toxicity that might be implied, the possible presented by aflatoxin in a peanut butter sandwich (0.03%). The FDA's
hazard from chlorinated substances is relatively low. Ameset al. (1987) authority to set tolerances has been used only once in establishing
levels for polychlorinated biphenyls (21 CFR 109.15 and 109.30).
most commonly associated with toxicity contained C18:3—anilide,
There have been only a few incidents of mass poisonings via
food, three of which involved contaminated cooking oil. The first also called oleyl anilide and “fatty acid anilide”) (Wood et al.,
became known as yusho, or rice oil disease, from rice oil contamina- 1994; Posada de la Paz et al., 1996; Borda et al., 1998).
tion by polychlorinated biphenyls (PCBs). This occurred in 1968 in
Japan and affected approximately 2000 individuals. The most vul-
Nitrosamines, Nitrosamides, and N-Nitroso Substances Ni-
nerable were newborns of poisoned mothers. The liver and skin were
trogenous compounds such as amines, amides, guanidines, and ureas
the most severely affected. Symptoms included dark brown pigmen-
tation of nails; acne-like eruptions; increased eye discharge; visual can react with oxides of nitrogen (NOx) to form N-nitroso com-
disturbances; pigmentation of the skin, lips, and gingiva; swelling of pounds (NOCs) (Hotchkiss et al., 1992). The NOCs may be divided
the upper eyelids; hyperemia of the conjunctiva; enlargement and into two classes: the nitrosamines, which are N-nitroso derivatives of
elevation of hair follicles; itching; increased sweating of the palms; secondary amines, and nitrosamides, which are N-nitroso derivatives
hyperkeratotic plaques on the soles and palms; and general- ized of substituted ureas, amides, carbamates, guanidines, and similar
malaise. Recovery requires several years (Anderson and Sogn, 1984; compounds (Mirvish, 1975).
Guo et al., 2003). The second incident occurred in 1979 in Yucheng, Nitrosamines are stable compounds, while many
Taiwan, which also involved PCB-contaminated cooking oil and nitrosamides have half-lives on the order of minutes, particularly at pH
exposed a similar number of people as the earlier incident in Japan ≫ 6.5. Both classes have members which are potent animal
(Guo et al., 2003). The third incident has become known as “Spanish carcinogens, but by different mechanisms. In general, the biological
toxic oil syndrome” and although details are still not activity of an NOC is thought to be related to alkylation of genetic
fully known, occurred when aniline-contaminated rapeseed oil was macro- molecules. N-nitrosamines are metabolically activated by
distributed as cooking oil in Spain in 1981. Approximately 20,000 hydroxylation at an α-carbon. The resulting hydroxyalkyl moiety is
people were affected and several deaths occurred. Because symptoms eliminated as an aldehyde, and an unstable primary nitrosamine is
were unique and included respiratory effects, eosinophilia and muscle formed. The nitrosamine tautomerizes to a diazonium hydroxide and
wasting, but not typical of aniline poisoning, the exact etiologic agent ultimately to a carbonium ion. Nitrosamides spontaneously
is still unknown. Because the source of the aniline may have been decompose to a carbonium ion at physiological pH by a similar
improperly cleaned tank trucks that had imported industrial mechanism (Hotchkiss et al., 1992). This is consistent with in vitro
chemicals, three hypotheses have been offered: the etiologic agent may laboratory findings because nitrosamines require S9 for activity and
have been (1) a contaminant in the aniline, (2) a contaminant nitrosamides are mutagenic de novo.
introduced during transportation or, (3) a reaction product of normal
oil components and the potential contaminants (the fraction of the oil
Table 30-23 Sources of Dietary NOCs
The use of nitrate and/or nitrite as intentional food additives, both of which are added
to fix the color of meats, inhibit oxidation, and prevent toxigenesis. Drying processes in which the drying air is heated by an open flame source. NOx is
generated in small amounts through the oxidation of N2, which nitrosates amines in the foods. This is the mechanism for contamination of malted barley pro
migrate from food contact materials such as rubber bottle nipples. NOCs can inhabit spices which may be added to food. Cooking over open flames (eg, natura
result in NOC formation in
foods by the same mechanism as drying.
SOURCE: Adapted with permission from Hotchkiss JH, Helser MA, Maragos CM, et al.: Nitrate, nitrite, and N-nitroso compounds: Food safety and biological implications, in Finley JW, Robinson SF, Armst
Assessment. Washington, DC, American Chemical Society, 1992, pp. 400–418.
consumption of H2-receptor blockers or antacids decreases

the formation of NOCs.
NOCs originate from two sources: environmental formation
and endogenous formation (Table 30-23). Environmental Environmentally, nitrite is formed from nitrate or ammonium
sources have declined over the last several years but still ions by certain microorganisms in soil, water, and sewage. In
include foods (eg, nitrate-cured meats) and beverages (eg, malt vivo, nitrite is formed from nitrate by microorganisms in the
beverages), cosmetics, occupational exposure, and rubber mouth and stomach, followed by nitrosation of secondary
products (Hotchkiss, 1989). NOCs formed in vivo may actually amines and amides in the diet. Sources of nitrate and nitrite in
constitute the greatest exposure and are formed from nitrosation the diet are given in Table 30-24. Many sources of nitrate are
of amines and amides in several areas, including the stomach, also sources of vitamin C. Another possibly significant source
where the most favorable conditions exist (pH 2 to 4), although of nitrate is well water; although the levels are generally in the
range of 21 μM, average levels of 1600 μM (100 mg/L) have from animals that consume contaminated feeds (eg, milk).
been reported (Hotchkiss et al., 1992). However, on the However, because commodities are eaten in the greatest
average, Western diets contain 1–2 mmol nitrate/person/day amounts, the mycotoxins present in these foods represent the
(Hotchkiss et al., 1992). Nitrosation reactions can be inhibited greatest risk (Cousins et al., 2005).
by preferential, competitive neutralization of nitrite with The current interest in mycotoxicosis was generated by a se-
naturally occurring and synthetic materials such as vitamin C, ries of reports in 1960–1963 that associated the death of turkeys
vitamin E, sulfamate, and antioxidants such as BHT, BHA, in England (so-called turkey X disease) and ducklings in
gallic acid, and even amino acids or proteins (Hotchkiss, 1989; Uganda with the consumption of peanut meal feeds containing
Hotchkiss et al., 1992). mold products produced by Aspergillus flavus (Stoloff, 1977).
N-nitrosoproline is the most common nitrosoamine present in The additional discovery of aflatoxin metabolites (eg, aflatoxin
humans and is excreted virtually unchanged in the urine. The
M1 in milk) led to more intensive studies of mycotoxins and
basal rate of urinary excretion of nitrosoproline, which is
claimed to be noncarcinogenic, is 2–7 g/d in subjects on a low to the identification of a variety of these compounds associated
nitrate diet (Oshima and Bartsch, 1981). Epidemiological with adverse human health effects, both retrospectively and
studies have not provided evidence of a causal association prospectively.
between nitrate exposure and human cancer nor has a causal Moldy foods are consumed throughout the world during times
link been shown between N-nitroso compounds, pre-formed of famine, as a matter of taste, and through ignorance of their
in the diet or endogenously synthesized, and the incidence of adverse health effects. Epidemiological studies designed to
human cancer (Gangolli, 1999). ascertain the acute or chronic effects of such consumption are
few. Data from animal studies indicate that the consumption of
Food-borne Molds and Mycotoxins Molds have served food contaminated with mycotoxins has the potential to
humans for centuries in the production of foods (eg, ripening contribute to a variety of human diseases (Miller, 1991).
cheese) and have provided various fungal metabolites with Reports of acute intoxications are few; however, prolonged
important medicinal uses; they also may produce secondary exposure to small quantities of mycotoxin may lead to more
metabolites with the potential to produce severe adverse insidious effects including growth retardation, birth defects,
health effects, including behavioral changes (Cousins et al., impaired immunity, decreased disease resistance, and tumor
2005). It is possible the ergot mycotoxins may have exerted a formation in humans and decreased production in farm
major role in restricting population expansion and only the animals (CAST, 2003).With some exceptions, molds can
reduced dependency on rye cereal as the staple food in
the sixteenth and seventeenth centuries, arising from the be divided into two main groups: “field fungi” and “storage
introduction of wheat and potatoes, allowed the steady upward fungi.” The former group contains species that proliferate in
movement in population growth (CAST, 2003; IFST, 2006a). and under field conditions and do not multiply readily once
Mycotoxins are secondary fungal metabolites (ie, not essential grain is in storage. Field fungi may be superseded and overrun
for survival of the mold) secreted into the microenvironment by storage fungi if conditions of moisture and oxygen allow.
around the mold. Mycotoxins represent a diverse group of Importantly, the presence of a toxigenic mold does not guaran-
chemicals that can occur in a variety of plants used as food, tee the presence of a mycotoxin, which is elaborated only under
including commodities such as cereal grains (barley, corn, rye, certain conditions. Further, more than one mold can produce
wheat), coffee, dairy products, fruits, nuts, peanuts, and spices. the same mycotoxin (eg, both Aspergillus flavus and several
A few mycotoxins also can occur in animal products derived Penicillium
Table 30-24 Nitrate and Nitrite Content of Food
NITRATE NITRITE NITRATE NITRITE VEGETABLES (ppm) (ppm) MEAT (ppm) (ppm)
Artichoke 12 0.4 Unsmoked side bacon 134 12 Asparagus 44 0.6 Unsmoked back bacon 160 8 Green beans 340 0.6 Peameal bacon
16 21 Lima beans 54 1.1 Smoked bacon 52 7 Beets 2400 4 Corned beef 141 19 Broccoli 740 1 Cured corned beef 852 9 Brussel
sprouts 120 1 Corned beef brisket 90 3 Cabbage 520 0.5 Pickled beef 70 23 Carrots 200 0.8 Canned corn beef 77 24 Cauliflower 480
1.1 Ham 105 17 Celery 2300 0.5 Smoked ham 138 50 Corn 45 2 Cured ham 767 35 Radish 1900 0.2 Belitalia (garlic) 247 5 Rhubarb
2100 NR Pepperoni (beef) 149 23 Spinach 1800 2.5 Summer sausage 135 7 Tomatoes 58 NR Ukranian sausage (Polish) 77 15 Turnip
390 NR German sausage 71 17 Turnip greens 6600 2.3
NR = not reported. SOURCE: Adapted with permission from Hotchkiss JH, Helser MA, Maragos CM, et al.: Nitrate, nitrite, and N-nitroso compounds: Food safety and biological
implications, in Finley JW, Robinson SF, Armstrong DJ (eds.): Food Safety Assessment. Washington, DC, American Chemical Society, 1992, pp. 400–418.
milk from dairy cows that consume contaminated feed. Aflatoxins
species produce the mycotoxin cyclopiazonic acid) (El-Bannaet al., may occur in a number of susceptible commodities and products
1987; Truckness et al., 1987). Also, more than one mycotoxin may be derived from them, including edible nuts (peanuts, pistachios,
present in an intoxication; that is, as in the outbreak of turkey X disease, almonds, walnuts, pecans, Brazil nuts), oil seeds (cottonseed, copra),
there is speculation that aflatoxin and cyclopiazonic acid both exerted and grains (corn, grain sorghum, millet) (Stoloff, 1977). In tropical
an effect, but the profound effects of aflatoxin would have regions, aflatoxin can be produced in unrefrigerated prepared foods.
overshadowed those of cyclopiazonic acid (Miller, 1989). Although The two major sources of aflatoxin contamination of commodities are
there are many different mycotoxins and subgroups (Table 30-25), this field contamination, especially during times of drought and other
discussion will be confined largely to six of the more toxicologically stresses, which allow insect damage that opens the plant to mold
and economically important: aflatoxins, trichothecenes, fumonisins, attack, and inadequate storage conditions. Since the discovery of their
zearalenone, ochratoxin A, and ergot alkaloids. potential threat to human health, progress has been made in
Organic foods, produced without the use of insecticides and decreasing the level of aflatoxins in specific commodities in
fungicides, may be more susceptible to mycotoxin contamination than developed countries. For example, in the United States and Western
foods produced using conventional agricultural practices. The UK European countries, control measures include ensuring adequate
Food Standards Agency found several organic maize meal products storage conditions and careful monitoring of susceptible commodities
highly contaminated with fumonisin mycotoxins whereas con- for aflatoxin level and the banning of lots that exceed the action level
ventional produced maize meal products analyzed concurrently had
levels below recommended limits (UK Food Standards Agency, 2003). for aflatoxin B1. Aflatoxin B1 is acutely toxic in all species
Because European agriculture faces a growing demand by consumers
studied, with an LD50 ranging from 0.5 mg/kg for the duckling to 60
for organic produce, the European Union has established a project
mg/kg for the mouse (Wogan, 1973). Death typically results from
called “safe organic vegetables and vegetable products by reducing risk
factors and sources of fungal contaminants throughout the production hepatotoxicity. Aflatoxin B1 is also highly mutagenic,
chain” focusing on organic carrots and reduction of alternaria toxins
(EU, 2002). hepatocarcinogenic, and possibly teratogenic. A problem in
extrapolating animal data to humans is the extremely wide range of
Aflatoxins Among the various mycotoxins, the aflatoxins have been species susceptibility to aflatoxin B1. For instance, whereas
the subject of the most intensive research because of the extremely
potent hepatocarcinogenicity and toxicity of aflatoxin B 1 in rats. aflatoxin B1 appears to be the most hepatocarcinogenic compound
Epidemiological studies conducted in Africa and Asia suggest that it is known for the rat, the adult mouse is essentially totally resistant to its
a human hepatocarcinogen, and various other reports have implicated hepatocarcinogenicity.
the aflatoxins in incidences of human toxicity (Krishna- machari et al.,
1975; Peers et al., 1976). Aflatoxin B1 is an extremely reactive compound
Generally, aflatoxins occur in susceptible crops as mixtures of
biologically, altering a number of biochemical systems. The
aflatoxins B1,B2,G1, and G2, with only aflatoxins B1 and G1
hepatocarcinogenicity of aflatoxin B1 is associated with its
demonstrating carcinogenicity. A carcinogenic hydroxylated
biotransformation to a highly
metabolite of aflatoxin B1 (termed aflatoxin M1) can occur in the
Table 30-25 Examples of Selected Mycotoxins Produced by Various Molds and Some of Their Effects and Commodities and Foods that are Potentially
COMMODITIES MYCOTOXIN SOURCE EFFECT CONTAMINATED
Aflatoxins B1, B2, G1, G2 Aspergillus flavus,
A. parasiticus
Acute aflatoxicosis, carcinogenesis
Corn, peanuts, and others
Aflatoxin M1 Metabolite of AFB1 Hepatotoxicity Milk Fumonisins B1, B2, B3,
B4, A1, A2
Fusarium verticillioides Renal and liver carcinogenesis Corn
Trichothecenes (for
example, T-2, deoxynivalenol, diacetoxyscirpenol)
Fusarium, myrothecium Hematopoietic toxicity,
meningeal hemorrhage of brain, “nervous” disorder, necrosis of skin, hemorrhage in mucosal epithelia of stomach and intestine, emesis, feed refusal, immune s
Cereal grains, corn
Zearalenones Fusarium Estrogenic effect Corn, grain Cyclopi azonic acid Aspergillus, Penicillium Muscle, liver, and splenic
toxicity
Cheese, grains, peanuts
Kojic acid Aspergillus Hepatotoxic? Grain, animal feed 3-Nitropropionic acid Arthrinium sacchari,
A. saccharicola, A. phaeospermum
Central nervous system
impairment
Sugarcane
Citreoviridin Penicillium citreoviride,
P. toxicarium
Cardiac beriberi Rice
Cytochalasins E, B, F, H Aspergillus and Penicillium Cytotoxicity Corn, cereal grain Sterigmatocystin Aspergillus versiolar Carcinogenesis Corn Penicillinic a
cyclopium Nephrotoxicity, abortifacient Corn, dried beans, grains Rubratoxins A, B Penicillium rubrum Hepatotoxicity, teratogenic Corn Patulin Penicillium p
Carcinogenesis, liver damage Apple and apple products Ochratoxin Aspergillus ochraceus,
A. carbonarius, Penicillium verrucosum
Endemic nephropathy,
carcinogenesis
Grains, peanuts, grapes, green
coffee
Citrinin Aspergillus and Penicillium Nephrotoxicity Cereal grains Penitrem(s) Tremors, incoordination, bl
Moldy cream cheese, English
walnuts, hamburger bun, beer Ergot alkaloids Clavicepts purpurea Ergotism Grains
reactive e lectrophilic epoxide, which forms covalent adducts with DNA, RNA, and protein. Damage to DNA is thought to be the initial biochemical lesion result
of the pathological tumor growth (IARC, 2002). Species differences in the response to aflatoxin may be due in part to differences in biotransformation and susce
biochemical lesion (Monroe and Eaton, 1987).
Trichothecenes Trichothecenes represent a group of toxic substances in which it is likely that several forms may be consumed concomitantly. They repr
chemical entities, all containing the trichothecene nucleus, and are produced primarily by Fusarium, but also by a number of commonly occurring molds, inc
Trichothecium, Stachybotrys, and Cephalosporium. The trichothecenes were first discovered during attempts to isolate antibiotics, and although some show anti
toxicity has precluded their use as therapeutic agents. Trichothecenes most often occur in moldy cereal grains. There have been many reported cases of trichoth
farm animals and a few in humans. One of the more famous cases of presumed human toxicity associated with the consumption of trichothecenes occurred in
around Orenburg, Siberia. Disruption of agriculture caused by World War II resulted in millet, wheat, and barley being overwintered in the field. Con- sumption o
resulted in vomiting, skin inflam- mation, diarrhea, and multiple hemorrhages, among other symptoms. About 10% of the population was affected and mortali
as 60% in some counties (Ueno, 1977; Beardall and Miller, 1994), and was subsequently identified as alimentary toxic aleukia (ATA) (CAST, 2003). Tricho
synthesis inhibitors known to bind to ribosomes. The extent of toxicity associated with the trichothecenes in humans and farm animals is poorly understood,
number of entities in this group and the difficulty of assaying for these compounds (JECFA, 2001). The acute LD 50s of the trichothecenes range from 0
though there have been reports of possible chronic toxicity associated with certain members of this group, more research will be needed before the magnitude
mechanism is a disruption of lipid metabolism by inhibition of
ceramide synthetase, an enzyme integral to the formation of complex
lipids for use in membranes (ICPS, 2000; IARC, 2002).Corn borer
produce adverse human health effects is understood (Sato and Ueno,
1977). insect pests cause damage to the developing grain, which enables
spores of the toxin-producing fungi, Fusarium, to germinate. The
Fumonisins Fumonisins are mycotoxins produced by Fusarium fungus then proliferates, which leads to ear and kernel rot and the
verticillioides (formerly known as F. moniliforme) and several other production of potentially hazardous levels of fumonisins. Corn
Fusariumspecies. Corn products contaminated withF. verticilliodes are varieties which express the Bt insecticidal protein recently have been
responsible for agriculturally important diseases in horses and swine shown to contain significantly reduced levels of fumonisin because the
(ICPS, 2000) and are actively being evaluated to determine how great Bt protein significantly reduces corn borer- induced tissue damage in
a threat they pose to public health. Initial evidence of the involvement corn products (Munkvold et al., 1997, 1999; Masoero et al., 1999;
of F. verticilliodes produced toxins in human disease, was reported by Hammond et al., 2004; Papst et al., 2005).
Marasas et al. (1988), who found that an increased incidence of
esophageal cancer was associated with the consumption of
Zearalenone Another mycotoxin produced by some Fusarium species
contaminated corn (maize) by humans in a region in South Africa.
is zearalenone. It was first discovered during attempts to isolate a
Fumonisins have been associated with cancer, reproductive toxicity
chemical from feeds that produced a hyperestrogenic syndrome in
(neutral tube defects), and acute disease outbreaks where low-quality
swine that was characterized by a swollen and edematous vulva and
corn is consumed on a regular basis (Cousins et al., 2005). Fumonisins
vaginal prolapse in severe cases (Stob et al., 1962). Zear- alenone can
target different organs in different species, but the underlying
occur in corn, barley, wheat, hay, and oats as well as other agricultural
commodities (Mirocha et al., 1977). Zearalenone consumption can of <5 mg/100 g of tuber fresh weight although a normal toxin load in
decrease the reproductive potential of farm animals, especially swine. the potatoes of 20–100 mg/kg tuber, is considered safe. The toxins are
not affected by baking, frying, or microwave cooking. SGAs inhibit
Ochratoxin A This mycotoxin is primarily produced by As- pergillus cholinesterases and can alter the effects of neuromuscular blocking
ochraceous, A. carbonarius, and Penicillium verrucosum and human drugs and anesthetics (Sorensen, 2002). Low doses of these
exposure occurs as the result of contamination of small grains (barley, glycoalkaloids can produce gastrointestinal upset with diarrhea,
wheat, corn), coffee beans and grapes. The effects of ochratoxin A were vomiting, and severe abdominal pain. At higher doses, neurological
discovered as the result of feeding the mycotoxin to pigs, who symptoms are evident with drowsiness and apa- thy, confusion,
subsequently drank copious amounts of water, urinated near weakness, and vision disturbances, followed by loss of consciousness
continuously, and exhibited pain in the area of the kidney. Ochratoxin and sometimes, death.
A is nephrotoxic and carcinogenic in mice and rats. Ochratoxin A is
Rodents do not absorb solanines well and the LD50 is >1000
absorbed from the gastrointestinal tract and enters the enterohepatic
circulation; it is also absorbed by the proximal and distal tubules of the mg/kg in mice and 590 in the rat; values that are 300–500 times more
kidney. It binds tightly to albumin in the blood and can therefore have than the toxic dose of 2 mg/kg in humans and, in which, the estimated
a very long serum half-life. Epidemiologic evidence indicates nearly lethal dose may be as little as 3–6 mg/kg. There was thought to be an
half the European population is exposed to ochratoxin A and there is association of potato (and SGA) consumption with neural tube defects
an association of endemic nephropathy and renal tumors in humans in children, although prospective studies have not borne out this
in parts of Eastern Europe (CAST, 2003). hypothesis, nor has this effect been seen in animal testing (ICPS, 1993).
In the 1960s, a scientist bred a new variety of potato, crossing
Ergot Alkaloids Produced by several species of Claviceps, these a Delta Gold with a wild type from Peru. The new variety called
mycotoxins are divided into four major groups based on chemical “Lenape” was excellent for making potato chips and was tested as a
structure: (1) clavines, (2) lysergic acids, (3) lysergic acid amides, and “new potato” for roasting with meats and vegetables. Upon eating the
(4) ergopeptines. There are two primary types of ergotism of humans, potato however, the grower was sickened and upon analysis, the potato
convulsive and gangrenous. Convulsive ergotism is typified by muscle was found to have high levels of glycoalkaloids. As a product of the
twitching and spasms, changes in mental state, hallucina- tions, breeding process, the gene for glycoalkaloids was stimulated to
sweating, and fever lasting for several weeks, all suggestive of produce a high level of SGA. Immediately, all the seed potato growers
serotonergic overstimulation of the CNS (Eadie, 2003). Postmortem were contacted and stocks were recalled or destroyed (Fedoroff and
findings include bleeding and softening of the brain and lesions in the Brown, 2004).
posterior horns of the spinal cord. Full mental recovery from a nonfatal
case is rare (Beardall and Miller, 1994). The gangrenous form of
Ethyl Carbamate Ethyl carbamate or urethane, the ethyl ester of
ergotism is characterized by edema, pruritis, necrotic extremities,
carbamic acid, was used for many years as an intravenous anesthetic
prickling sensations, and severe muscular pain (CAST, 2003), all of
until its mutagenic and carcinogenic properties became known. It has
which are likely the result of peripheral vasoconstric- tion.
since been classified by the International Agency for Re- search on
Cancer (IARC) as “possibly carcinogenic to humans” (Group 2B) and
Solanine and Chaconine The humble potato, Solanum tuberosum, “reasonably anticipated to be a human carcinogen” by the National
may produce toxic steroidal glycoalkaloids if exposed to light in the Toxicology Program (NTP, 2004a). The primary use of urethane is as
field or during storage or otherwise stressed by mechanical damage or a chemical intermediate in the preparation of amino resins, with lesser
improper storage or sprouting. Previously known only as “solanine” uses as a solubilizer in the manufacture of pesticides, fumigants, and
or now, (total) solanaceous glycoalkaloids (SGA), the major players cosmetics and as an intermediate for pharmaceuticals and biochemical
are α-solanine and α-chaconine and are normally present in amounts research. It is allowed in some
beverages range from a mean of 0.015 μg/kg BW/d to 0.080
μg/kg BW/d for high-end users. The BMDL (benchmark dose
lower confidence limit) as set by JECFA is 0.3 mg/kg BW/d,
anticonvulsant drugs at a level of 1 ppm and is still used as a which yields a margin of safety of 20,000 (JECFA, 2005).
vet- erinary anesthetic. Urethane has been found in fermented
foods and beverages including liquor, wine, beer, bread, soy
Trans Fatty Acids Trans fatty acids, also known as trans fat,
sauce, and yogurt. Diethylpyrocarbonate, an inhibitor of
are made through the process of hydrogenation of unsaturated
fermentation, can form ethyl carbamate.
bonds that solidifies (liquid) oils. Hydrogenation increases the
Ethyl carbamate is easily absorbed and undergoes CYP2E1-
melting point, shelf life, and flavor stability of these oils and
mediated metabolic activation to vinyl carbamate epoxide,
foods that contain them. The hydrogenation process was
which binds covalently to nucleic acids and proteins, producing
developed in the 1930s and has been in widespread commercial
adducts. Ethyl carbamate is a multisite carcinogen with a short
use since the 1940s. Dietary fats containing hydrogenated fatty
latency period. Single doses or short-term oral dosing at 100–
acids, such as those used in margarine, have gradually
200 mg/kg BW/d has been shown to induce tumors in mice,
displaced animal fats, such as butter and lard. Trans fat is found
rats, and hamsters. Intake estimates from food and alcoholic
in vegetable shortenings, and in some margarines, crackers,
cookies, snack foods, and other foods. The scientific literature are reversible within hours or days, whereas 80 μg of purified
is replete with studies indicating that consumption of trans fatty toxin per 100 g of tissue (0.5–2 mg/person) may be lethal, due
acids contributes to increased blood LDL-cholesterol (“bad” to as- phyxiation, usually within 12 hours of ingestion. The
cholesterol) levels, which increase the risk of coronary heart toxin is an alkaloid and is relatively heat stable. The toxin is
disease (CHD). Recent information from the American Heart produced by several genera of plankton (Gonyaulax (now
Association indicates that CHD causes about 500,000 deaths known as Alexandrium) catenella, G. acatenella, and G.
annually, making it the number one cause of death in the United tamarensis, Pyrodinium spp., Pty- chodiscus brevis,
States (FDA, 1999a,b). To remedy this problem, it is now Gymnodinium catenaturm and others), and during red tide
required to label foods indicating the amount of trans fat blooms may reach 20 million to 40 million per milliliter. Toxic
present. materials are stored in various parts of the body of shellfish.
Digestive organs, liver, gills, and siphons contain the greatest
concentrations of poison during the warmer months.
Furan Furan was once known only as an industrial chemical
Distribution is worldwide (Bryan, 1984; Clark et al., 1999;
intermediate in the synthesis of polymers used to prepare
Liston, 2000). The tolerance for PSP for clams, mussels, and
temperature- resistant structural laminates and to prepare
oysters is 80 μg/100 g of meat (Compliance Policy Guideline,
copolymers used in machine dishwashing products. Furan has
540.250).
recently been found to occur in a number of foods that undergo
heat treatment, such as canned and jarred foods, including baby
food. It is considered by IARC (1995) to be possibly
carcinogenic to humans. According to the NTP, furan is Added Substances—Fluoride Fluorine, in the form of
hepatotoxic and shows clear evidence of carcinogenicity to fluoride, is nearly ubiquitous in nature. Primary human
both sexes and both species of mice and rats (NTP, 1993). Furan exposure is via drinking water, although it is also present in
is produced in a variety of experimental systems, including some foods, notably some teas, vegetables, and marine fish.
heating of sugars (eg glucose, lactose, fructose, xylose, Exposure also occurs via processed food made with fluoridated
rhamnose), heating sugars in the presence of amino acids or water or produce washed with fluoridated water (the so-called
protein (eg, alanine, cysteine, casein), and thermal degradation 'halo' effect). The greatest nondietary source is fluoridated
of vitamins (ascorbic acid, dehydroascorbic acid, thiamin) toothpaste (NRC, 2006). Fluoride taken in water has a high
(FDA, 2004). degree of bioavailability with an absorption of 90% and with
food, approximately 50%. Consumption of fluoride results in
Furan has been found in a small number of heat-treated foods,
uptake by bone and in teeth, where enamel crystallites form flu-
including coffee, canned meat, baked bread, cooked chicken,
orhydroxyapatite in place the naturally formed hydroxyapatite;
sodium caseinate, filberts (hazelnuts), soy protein isolate,
the former being stronger and more acid resistant than the latter,
hydrolyzed soy protein, rapeseed protein, fish protein
re- sisting and even reversing the initiation and progression of
concentrate, and caramel (FDA, 2004). Very little information
dental caries. Ionic fluoride rarely exists in blood, most is
has been developed on furan levels in food.
trapped by bone tissue, where new bone growth is stimulated
and this mechanism has served as the basis of some treatments
Dinoflagellate Poisoning (Paralytic Shellfish Poisoning or
for osteoporosis (WHO, 1996).Fluorosis occurs as the result
PSP; Saxitoxin) In contrast to other seafood toxins, there is a
tolerance set for PSP. The etiologic agent in this type of of high fluoride intake and may be complicated by low
poisoning is saxitoxin calcium intake; it is cumulative and endemic to some areas of
or related compounds and is found in mussels, cockles, clams, the world (eg, China and India). Fluorosis is dose responsive,
soft shell clams, butter clams, scallops, and shellfish broth. producing a range of effects from cosmetic (mottling of teeth)
Bivalve mussels are the most common vehicles. Saxitoxin, to adverse functionality (skeletal fluorosis). Enamel fluorosis
originally isolated from toxic Alaskan butter clams (Saxidomus occurs as the result of high fluoride consumption prior to tooth
giganticus) is actually a family of neurotoxins and includes eruption (ie, in children up to the age of eight years, exposed to
neosaxitin and gonyautoxins 1 through 4. All block neural water with a fluoride content of ≥4 mg/L) and can range from a
transmission at the neuromuscular junction by binding to the mild discoloration of the tooth surface to severe (brown)
surface of the sodium channels and in- terrupting the flow of staining and pitting of the teeth to the point of enamel loss
Na+ ions; AV nodal conduction may be sup- pressed, there may (NRC, 2006). In skeletal fluorosis, in the asymptomatic,
be direct suppression of the respiratory center and progressive preclinical stage, patients have an increased bone density. Stage
reduction of peripheral nerve excitability. The toxin produces 1 skeletal fluorosis is characterized by occasional stiffness,
parathesia and neuromuscular weakness without hypotension pain in joints or some osteosclerosis of the pelvis and vertebra.
and lacks the emetic and hypothermic action of tetrodotoxin. Stage 2 skeletal fluorosis is characterized by sporadic pain,
Moderate symptoms are produced by 120–180 μg/person and stiffness of joints and osteosclerosis of the pelvis
location of the poison. For example, (1) ichthyosarcotoxin is con-
centrated in the muscles, skin, liver, or intestines or is otherwise not
associated with the reproductive system or circulatory system, (2)
and spine, although mobility is not severely affected. In Stage 3 (rarely ichthyootoxin is associated with reproductive tissue, (3) ichthyohe-
seen in the US), there may be crippling, dose-related calci- fication of motoxin is confined to the circulatory system, and (4) ichthyohepa-
ligaments, osteosclerosis, exotoses, osteoporosis of long bones, muscle totoxin is confined to the liver. In general, seafood toxins under FDA
wasting, and neurological effects due to hypercalci- fication of policy have a zero tolerance, with any detectable level considered
vertebrae (at this point, bone ash fluoride may be 2–3 times that of the cause for regulatory action.
bones of normal subjects). While it is agreed that skeletal fluorosis is
the result of prolonged exposure to increased amounts of fluoride,
because the incidence of crippling skeletal fi- brosis continues to be Neurotoxic Shellfish Poisoning (NSP) Traditionally limited to the
rare even in geographic areas of high exposure, unidentified coast of Florida, Gymnodinium breve form red tide blooms containing
intervening metabolic or dietary factors may have rendered skeletons polycyclic ether toxins called brevetoxins (based on the back- bone
more or less susceptible. Other effects attributed to excess fluoride structure of the molecule generally divided into Type 1 or Type 2), with
include lower IQ's and decreased thyroid function, increased calcitonin Type 2 the most often found. Brevetoxins bind to voltage-dependent
activity, increased parathyroid hormone activity, secondary sodium channels and strength of binding varies with the specific
hyperparathyroidism, impaired glucose tolerance and possible effects affinity of the toxin and thus the relative potency. Symptoms of NSP
on timing of sexual activity (NRC, 2006). The reports of possible include nausea, tingling, and numbness of the oral area, loss of motor
carcinogenic effects of fluoride are mixed and inconclusive. control and severe muscular ache; all of which resolve in a few days
and no deaths have been reported, unlike PSP. An additional route of
Guidelines for fluoridation of the public water supply
entry for mammals may result from inhalation of aerosolized toxin as
recom- mend addition at levels of 0.7–1.2 mg/L, to achieve target
the result of the relative ease of lysis of the unarmored G. breve
Adequate Intake levels based on a 2 L water/day intake by adults; with
organism during the breaking of waves on the shore. Symptoms of this
adjustments in warmer regions where water intake is high in the
type of exposure are seen as irritation of the throat and upper
summer months, or where fluoride occurs naturally at high levels (eg,
respiratory tract. A “kill” of nearly 150 manatees was reported during
some areas of Colorado, 11.2 mg/L; Oklahoma, 12.0 mg/L; New Mex-
an unprecedented large outbreak of the toxin, although the specific
ico, 13.0 mg/L; and Idaho, 15.9 mg/L). Although the essentiality of
mode of transmission is uncertain. Human exposure is primarily via
fluorine has not been described, an Adequate Intake (AI) has been
consumption of filter- feeding organisms, which may concentrate the
established for various age groups as a balance between caries
toxin (Van Dolah, 2000).
resistance and possible fluorosis of teeth. For example, the AI for
infants at 0.01 mg/d, for adult females and males at 3 and 4 mg/d, re-
spectively and, a range of graduated AI's for intervening age groups Amnesic Shellfish Poisoning (Domoic Acid) Consumption of
(IOM, 1997). mussels harvested from the area off Prince Edward Island in 1987
resulted in gastroenteritis and many older consumers or those with
underlying chronic diseases, experienced neurologic symptoms in-
SUBSTANCES FOR WHICH TOLERANCES cluding memory loss. Despite treatment, three patients (71–84 years
MAY NOT BE SET old) died within 11–24 days. The poisoning was attributed to domoic
acid produced by the diatom Nitzschia pungens f. multiseries (now
All the contaminants of food described to this point are those associ- called Pseudonitzschia multiseries) which had been ingested by the
ated with synthesis, growth, production, or storage and are regarded by mussels during the normal course of feeding. Occurrence of domoic
FDA asunavoidable. Because they are unavoidable, the FDA sets limits acid has also been reported in California shellfish and produced byN.
rather than bans them, as described earlier. The substances in this pseudodelicatissima and in anchovies (resulting in pelican deaths)
section are regarded as (1) avoidable or of such hazard that a safe level produced by N. pseudoseriata (now called Pseudonitzchia aus- tralis).
cannot be set and as such, FDA has determined that food containing Domoic acid has been reported in shellfish in other provinces of
such substances is banned or; (2) are beyond the control of FDA and Canada, Alaska, Washington, and Oregon and may be as frequent as
cannot be regulated (eg, substances produced in the home). PSP toxins. Domoic acid has also been reported in seaweed. Do- moic
acid was reported in Japan in 1958 and was isolated from the red algae
Chondria armata.
Toxins in Fish, Shellfish, and Turtles In the Canadian outbreak, mice injected with extracts (as in
the PSP assay) died within 3.5 hours. The mice exhibited a scratching
There are a number of seafood toxins (to be distinguished from ma-
syndrome uniquely characteristic of domoic acid that was followed by
rine venoms), many of which are not confined to a single species (over
increasingly uncoordinated movements and seizures until the mice
400 species have been incriminated in ciguatera toxicity) and are
died. Levels of domoic acid >40 μg/g wet weight of mussel meat
therefore most likely to be influenced by the environment. How- ever,
caused the mouse symptoms (Canadian authorities require ces- sation
some seafood toxins are specific to a single species or genus. A
of harvesting when levels approach 20 μg/g). Mice and rats can
complicating factor in the study of seafood toxins is the sporadic
generally tolerate 30–50 mg/kg. Domoic acid is dose-responsive in
frequency and nonpredictability of the presence of the toxin.
humans: with no effect at 0.2–0.3 mg/kg, mild gastrointestinal
Seafood toxins generally can be classified according to the
symptoms at 0.9–2.0 mg/kg, and the most serious symptoms at 1.9– 4.2
mg/kg with gastrointestinal effects and neurological effects, including kainic acid; the toxicity of all three are similar as they are excitatory
dizziness, disorientation, lethargy, seizures, and permanent loss of and act on three types of receptors in the CNS with the hippocampus
short-term memory. Although rodents appear to be more tolerant, the being the most sensitive. Domoic acid may be a more potent activator
fatalities in humans were likely associated with underlying illness. of kainic acid receptors than kainic acid itself.
Domoic acid is an analog of glutamine, a neurotrans- mitter and of
smeared the moss on spear points to enhance their utility as a
weapon (Onuma et al., 1999; Tan and Lau, 2000; Tosteson,
2000).
The stimulatory action may lead to extensive damage of the hip- The toxin has been reported in mackerel, parrotfish, and several
pocampus, but less severe injury to the thalamic and forebrain species of crabs. Victims report a bitter, metallic taste from the
regions (Todd, 1993; Clark et al., 1999; Van Dolah, 2000). meat (most often muscle, liver, ovary, and digestive tract),
followed immediately by nausea, vomiting, and diarrhea.
Ciguatera Poisoning The “cigua” in ciguatera toxin is derived Within several hours, symptoms include myoglobinuria, a
from the Spanish name for the sea snail Turbo pica in which the burning sensation around the mouth and extremities, muscle
symptoms were first reported. Ciguatera and related toxins spasms, dyspnea, and dysphonia. Cause of death may be the
(scar- itoxin and maitotoxin) are ichthyosarcotoxic neurotoxins result of mycocardial injury, although it is known in vitro to be
(anti- cholinesterase) and are found in 11 orders, 57 families, a powerful hemolysin.
and over 400 species of fish as well as in oysters and clams. The Although there are several isoforms and possibly minor toxins
penultimate toxin (gambiertoxin) is produced by the associated with palytoxin (depending on the producing
dinoflagellate Gambierdis- cus toxicus, commonly isolated species), the predominant action is as a oubain-sensitive
from microalgae growing on or near coral reefs that have Na+K+-ATPase inhibitor. Unlike oubain, palytoxin has no
ingested the dinoflagellate. The pre-toxin appears to pass effect on H+-, Ca2+-, or H+/K+-transporting ATPases. The toxin
through the food chain and is biotransformed upon transfer to
is quite effective with intravenous LD50s of 0.078, 0.45,
or by the ingesting fish to the active, which is consumed by
mammals. Other toxins, including palytoxin and okadaic acid, 0.033, and 0.089μg/kg for monkeys, mice, dogs, and rats,
unrelated to gambiertoxin, may be present in ciguarteric fish
respectively. The standard assay is measured in
and may contribute to toxicity. The asymptomatic period is 3–
mouse units (MU), the time taken to kill a mouse weighing 20
5 hours after consumption but may last up to 24 hours. The
grams in 4 hours following intraperitoneal (ip) injection of 0.25
onset is sudden, and symptoms may include abdominal pain,
mL (Tan and Lau, 2000; Tosteson, 2000).
nausea, vomiting, and watery diarrhea; muscular aches; tingling
and numbness of the lips, tongue, and throat; a metallic taste;
temporary blindness; and paralysis. Deaths have occurred. Puffer Fish Poisoning (Tetrodotoxin) Tetrodonor puffer fish
Recovery usually occurs within 24 hours, but tingling may poisoning is caused by the improper preparation and
consumption of any of about 90 species of puffer fish (fugu,
continue for a week or more. The intraperitoneal (ip) LD50 of
blowfish, globefish, por- cupine fish, molas, burrfish,
maitotoxin in mice is 50 ng/kg (Bryan, 1984; Liston, balloonfish, toadfish, etc.); although the toxin has also been
reported present in newts, frogs, octopus, starfish, flatworms,
2000).
various crabs, and gastropods. Pufferfish are found in
subtropical and tropical marine waters in the Atlantic (including
Palytoxin Poisoning Palytoxin is produced by the zoanthind off the coast of Florida), Pacific, and Indian Oceans. Some
soft coral of the genus Palythoa, and fish, crabs, and polychaete puffers live in brackish and fresh water. The toxin
worms living in close association with or eating this mass, may (tetrodotoxin) is located in nearly all the tissues, but the ovaries,
become contaminated with palytoxin. The toxin is not part of roe, liver, intestines, and skin are the most toxic. Toxicity is
the stinging nematocyst of the coral, but may be produced by highest during the spawning period, although a species may be
female polyps and mature eggs of the organism, possibly toxic in one location but not in another. Tetrodotoxin is
requiring the presence of an unidentified symbiotic algae associated with the presence of several bacteria on and in fish
(possibly the dinoflagellate Ostreopsis siamensis). Palytoxin, in and shellfish and is an evolutionary advantage providing
various forms, is produced by any number of species, including protection against predators (ie, they are endosymbiotic
P. tuberculosa in the tropical waters in the Pa- cific and bacteria). A total of 21 species can produce tetrodotoxins
Japan,P. mammilosaandP. caribaeorumin the West Indies, including Vibros, Pseudomonas, and E. coli, and at least two
Puerto Rico, and the Bahamas, P. vestitus and other Palythoa strains of red algae.
spp. On occasion, the coral becomes detached from its Tetrodotoxin is a neurotoxin and causes paralysis of the central
anchorage and becomes a soft floating mass with a seaweed or nervous system and peripheral nerves by blocking the
moss-like appearance, a very attractive feeding ground for movement of all monovalent cations. The toxin is water-soluble
fish. Indigenous peoples of Hawaii knew this as limu-make-o- and is stable to boiling except in an alkaline solution. A fatal
Hana (the deadly seaweed of Hana) and some are said to have dose may be as little as 1–4 mg/person. The victim is
asymptomatic for 10–45 minutes but may have a reprieve for as heat, acidic or alkaline media (Randall et al., 1981). The skin
long as 3 or more hours. Toxicity is manifested as a tingling or mucous of other species of eels, the common European eel
prickly sensation of the fingers and toes; malaise; dizziness; (Anguilla anguilla) and pike eel (Muraenesox cinereus) were
pallor; numbness of the lips, tongue, and extremities; ataxia; found to have proteinaceous toxins, immunologically similar to
nausea, vomiting, and diarrhea; epigastric pain; dryness of the that of the skin mucous toxin from the Japanese eel (Anguilla
skin; subcutaneous hemorrhage and desquamation; respiratory japonica) (Shiomi et al., 1994).
distress; muscular twitching, tremor, incoordination, and
muscular paralysis; and intense cyanosis. Fatality rates are high
Abalone Poisoning (Pyropheophorbide) Abalone poisoning
(Bryan, 1984; Liston, 2000).
is caused by abalone viscera poison (located in the liver and
digestive gland) and is unusual in that it causes
Moray Eel Poisoning Although the moray eel (Gymnothorax photosensitization. The toxin, pyropheophorbide a, is stable to
javanicus) and other carnivorous fishes may accumulate boiling, freezing, and salting. It is found in Japanese abalone,
ciguatoxin as the result of eating other contaminated fish, the Haliotis discus and H. sieboldi. The development of symptoms
Indo-Pacific moray eel (Lycodontis nudivomer) has been shown is contingent on exposure to sunlight. The symptoms are of
to possess a mucous skin secretion with hemolytic, toxic and sudden onset and include a burning and stinging sensation
hemagglutinating properties, unrelated to ciguatoxin. The over the entire body, a prickling sensation, itching, erythema,
hemolytic properties can be separated from the edema, and skin ulceration on parts of the body exposed to
hemagglutinating properties. The hemolytic property is lost sunlight (Bryan, 1984; Shiomi, 1999). Paralytic shellfish toxin
upon treatment with trypsin and is unstable in the presence of
lowing consumption of certain types of fish found in both salt and fresh
water. The syndrome consists of rhabdomyolysis with a release of
muscle cell contents into the blood. Patients are often rigid, sensitive
(PST) has been detected in abalone, probably through consumption of to touch and unable to move; urine may have a dark brown color.
the mossworm, a plankton feeder that also clings to seaweed and some Symptoms appear 18 hours (with a range of 6–21 hours) after
shellfish (Takatani et al., 1997). consumption; symptoms resolve within 2–3 days and the fatality rate
is approximately 1% (Frenzen, 2004). “Haff disease” was first reported
Sea Urchin Poisoning The etiologic agent forms during the re- in the 1920s along the Koenigsberg Haff, a brackish inlet on the Baltic
productive season and is confined to the gonads. The sea urchins in- sea, although outbreaks have been reported in Swe- den, the former
volved include Paracentrotus lividus, Tripneustes ventricosus, and Soviet Union and in the United States beginning in 1984. US
Centrechinus antillarum. The symptoms include abdominal pain, poisonings have been associated with buffalo fish (Ictiobus cyprnellus)
nausea, vomiting, diarrhea, and migraine-like attacks (Bryan, 1984). caught in California, Missouri, and Louisiana. No etiologic agent has
The toxin has been shown to interfere with calcium uptake in nerve been identified (Anonymous, 1998).
preparations (Zhang et al., 1998).
Microbiological Agents—Preformed Bacterial
Sea Turtle Poisoning (Chelonitoxin) The etiologic agent here is Toxins
chelonitoxin, which is found in the liver (greatest concentration) but
also in the flesh, fat, viscera, and blood. Toxicity is described as spo- Although the United States likely has the safest and cleanest food
radic or even seasonal, indicating the poison may be derived from toxic supply in the world, most food-related illness in the United States
marine algae. Most outbreaks occur in the Indo-Pacific region. The results from microbial contamination. Food-borne disease outbreaks
turtles involved include the green sea turtle, the hawksbill and are tracked by the Centers for Disease Control and Prevention (CDC)
leatherback turtles. Local custom in Sri Lanka is to first offer the liver in Atlanta, Georgia. The CDC reports that there are approximately 400
to crows and if the birds eat it, the flesh is regarded as safe, but because outbreaks of food-borne disease per year involving 10,000– 20,000
the symptoms appear over a few hours to several days, this bioassay people. However, the actual frequency may be as much as 10– 200
requires patience. Symptoms of intoxication in humans include times as high because (1) an outbreak is classified as such only when
vomiting; diarrhea; sore lips, tongue, and throat; foul breath, difficulty the source can be identified as affecting two or more people and (2)
in swallowing; a white coating on the tongue, which may become most home poisonings are mild or have a long incubation time
covered with pin-sized, pustular papules; tightness of the chest; coma; and are therefore not connected to the ingested food, go unreported and
and death. The toxin has been reported transferred to nursing infants are often felt to be only a “24-hour bug.” Naturally, because of
from intoxicated mothers. Post-mortem exami- nations reveal differences in virulence and opportunity, some species are more likely
congestion of internal organs, interstitial pulmonary edema, and than others to cause outbreaks.
necrosis of myocardial fibers. Fatality rates of 7% and 25% have been If all the microbiological food-borne health concerns could
reported (Bryan, 1984; Ariyananda and Fernando, 1987; Chandrasiri et be divided into two categories—poisoningsandinfections—the former
al., 1988; Champetier De Ribes et al., 1997). would include chemical poisonings and intoxications, which may have
a plant, animal, or microbial origin. In the infections category, food
acts as a vector for organisms that exhibit their pathogenicity once they
Haff Disease Haff disease is a syndrome of unknown etiology fol-
have multiplied inside the body. Infections include the two not an integral part of the organism, but may enhance its virulence.
subcategories: enterotoxigenic infections (with the release of toxins Some bacteria, such as Shigella spp., Staphylococ- cus aureus, or
following colonization of the GI tract) and invasive infections in Escherichia coli (which releases the shiga-like vero toxin), can
which the GI tract is penetrated and the body is invaded by organisms. elaborate both endotoxin and exotoxin.
There are a number of food toxins of microbial origin; how-
ever, discussion in this chapter will be limited to pre-formed bacterial
toxins—that is, those toxins elaborated by bacteria concomitant to their Clostridium Botulinum, C. butyricum and C. baratti Food botulism
residence and growth in or on the food prior to ingestion. Importantly, rarely causes illness because the confluence of conditions required for
the bacteria need not be present for the intoxication to take place its germination and toxin production—low acidity, high water activity,
because the bacteria may have been killed by heat while the toxin absence of preservatives, ambient temperature, and anaerobic
survives. Bacterial toxins may be divided on the basis of activity: environment—such a combination rarely occurs in foods, but
emetic toxins (ie, Bacillus cereus), which produce their effect by botulinum poisoning remains important, the result of its potency
binding to specific receptors in the duodenum, neurotoxins (whose (Sobelet al., 2004). AllClostridiaare Gram-positive, spore-forming
action is self explanatory) and, enterotoxins, which are protein toxins anaerobes. Botulism is a product of the toxins: A (the predominant
having action on the enteric cells of the intestine. Enterotoxins can be form in the US), B (the predominant form in Europe), E (the pre-
subdivided into cytotoxic enterotoxins which disrupt the cell dominant form in Northern latitudes), and F that may be produced by
membrane or other vital functions of the cell and cytotonic one or more strains of C. botulinum, C. butyricum (Type E only) andC.
enterotoxins, which enter the epithelial cell and cause diarrhea baratti; toxins C and D cause botulism in animals. Type G has not
without direct membrane disruption or cell death (Granum, 2006). caused any human cases. C. botulinum toxins are categorized as Group
Bacterial toxins may also be divided on the basis of their origin: an I to IV on the basis of toxin produced; additionally, Group I is
endotoxin is generally a lipopolysaccharide membrane constituent proteolytic in culture (liquefying egg white, gelatin, and other solid
released from a dead or dying Gram-negative bacteria, these toxins are proteins). The toxin is elaborated in foods, wounds, and infant gut and
nonspecific and stimulate inflammatory responses from macrophages is neurotoxic, interfering with acetylcholine at peripheral nerve
including, but not limited to prostaglandins, throm- boxanes, endings. Botulinum neurotoxins induce blockage of voluntary motor
interleukins, and other mediators of immunity; exotoxins which are and autonomic cholinergic neuromuscular junctions, which
synthesized and released (usually by Gram-positive bacteria) and are
bioassay and an enzyme-linked immunosorbent assay (ELISA).
The mouse bioassay is the accepted standard, where the mouse
is injected with a lethal dose, the signs of which should develop
prevents motor fiber stimulation. Clinical illness is in 8 hours and, if not, the mouse is observed for 4 days. The
characterized by cranial nerve palsies, followed by descending mouse bioassay can also be used to differentiate between the
flaccid muscle paralysis, which can involve the muscles of toxin types by mixing neutralizing antibodies with the sample,
respiration. Although ptosis and dysarthria may be mistaken for prior to injection. Determining which mice survive following
signs of encephalopathy, patients are fully alert, and the results which combination of toxin and antis- era, determines the
of a sensory examination are normal. Recovery often takes specific toxin type. The absolute amount of toxin detected in
weeks to months (Sobel et al., 2004). Although the spores are the mouse bioassay is not well defined but is thought to be 10–
among the most heat-resistant, the toxins are heat-labile (the 20 pg/mL for type A (Barr et al., 2005).
toxin may be rendered harmless at 80–100◦C for 5–10 minutes). Sources and reservoirs for Clostridia include soil, mud, water,
Botulinum toxins are large zinc-metalloproteins of ∼150,000 and the intestinal tracts of animals. Foods associated with
Da, composed of two parts, a 50,000 Da piece, the cat- alytic botulinum toxin include improperly canned low-acid foods
subunit and the 100,000 Da piece containing an N-terminal (green beans, corn, beets, asparagus, chili peppers, mushrooms,
translocation domain and a C-terminal binding domain. The spinach, figs, baked potato, cheese sauce, beef stew, olives, and
structural features are similar to tetanus toxin. For Types B, tuna). The toxin also may occur in smoked fish, fermented food
D, F, and G (and tetanus toxin), the target protein is (seal flippers, salmon eggs) and improperly home-cured hams.
VAMP/synaptobrevin, a protein associated with the synaptic An increasing source of poisonings is from the use of flavored
vesicle. Types A and E cleave a protein associated with the oils or oil infusion, most typically in garlic-in-oil preparations;
presynaptic membrane, ANAP25. Bo- tulinum toxin C cleaves in 1993, FDA required acid- ification of such preparations to
SNAP25 and syntaxin, another protein involved in exocytosis. prevent the growth of Clostridia. Whereas a proteolytic strain
Although intracellular mechanisms of botulinum and tetanus of C. botulinum (Group I) may cause the food to appear and
toxins are similar, symptoms are different because different smell “spoiled” (by-products include isobu- tyric acid,
populations of neurons are targeted. The symptoms may isovaleric acid, and phenylpropionic acid), this is not the case
include respiratory distress and respiratory paralysis that may with nonproteolytic strains, many of which can flourish and
persist for 6–8 months. The case fatality rate in the United elaborate toxin at temperatures as low as 3◦C (Loving, 1998;
States is 4% (Sobel et al., 2004) and the poison is fatal in 3–10 Belitz and Grosch, 1999; Crane, 1999; Lund and Peck, 2000).
days; a lethal dose is approximately one nanogram.
The successful use of nitrates in meat to prevent spoilage by C.
Current methods for detecting botulinum toxin include a mouse botulinum resulted in the petitioning of FDA by the USDA to
have sodium and potassium nitrate approved for addition by lysis, and villi tip desquamation and severe fluid loss. This is
“prior sanction” (21 CFR 181.33). The mechanism of nitrates manifested by abdominal cramping and diarrhea occurs within
is believed to be due to an inactivation by nitric oxide of iron– 8–16 hours, although symptoms are of short duration, one day
sulfur proteins such as ferrodoxin and pyruvate oxidoreductase or less. Foods associated with C. perfringens poisoning include
within the germi- nated cells. The activity is dependent on the cooked meat or poultry, gravy, stew, and meat pies. C.
perfringens is also associated with the production of another 11
pH and is proportional to the level of free HNO2; 100 mg
toxins, including those associated with gas gangrene (Hobbs et
nitrate/kg of meat is necessary for the antimicrobial effect, al., 1953; Hauschild, 1971; Walker, 1975; Hobbs, 1976; Crane,
1999; Labbe, 2000).
although this effect can be enhanced with ascorbates and
chelating agents. Other antibacterials that pre-
vent C. botulinum include nisin (used in cheese spreads),
parabens, phenolic antioxidants, polyphosphates, and carbon Bacillus cereus Bacillus cereus is also a Gram-positive, spore-
dioxide (Belitz and Grosch, 1999; Lund and Peck, 2000). forming rod, but is an aerobe. Bacillus cereus is a causative
agent of emetic or diarrheagenic exo- and enterotoxins
elaborated in food. The emetic thermostable toxin (surviving
Clostridium perfringens Unlike C. botulinum, the primary 259◦F for 90 minutes) is called cerulide (a small cyclic peptide,
reservoir for C. perfringens is the intestinal tract of warm- 1.2 kDa that acts on 5-HT3 receptors stimulating the vagus
blooded animals (including humans). Most incidences of C. afferent nerve) and is produced by serotypes 1, 3, and 8; it is
perfringens food poisoning are associated with the also resistant to pH and proteolysis, but is not antigenic. The
consumption of roasted meat that has been contaminated with diarrheagenic thermolabile toxin (133◦F for 20 minutes), is
intestinal contents at slaughter, followed by roasting and produced by serotypes 1, 2, 6, 8, 10, and 19; and may also be
inadequate storage, allowing C. perfringens growth and produced in situ in the lower intestine of the host. The diarrheal
enterotoxin (CPE) to be elaborated (although some CPE may form may actually consist of three toxins, one of which is
actually be released during a “second sporulation” process in hemolytic (Granum, 2006). Reservoirs are soil and dust. Foods
the stomach of the victim). Virtually all food poisoning is associated with this organism and its toxic properties, include
produced by type A strain, although a particularly severe form boiled and fried rice (principally the emetic form), while the
(a necrotic enteritis called “pig-bel” among indigenous peoples diarrheal form has a wider occurrence and may be found in
of the New Guinea high- lands or in Germany known as meats, stews, pudding, sauces, dairy products, vegetable dishes,
“Darmbrand”) and is produced by type C strain, which has a soups, and meat loaf (Goepfert et al., 1972; Gilbert, 1979;
mortality rate of 15–25% even with treatment. The toxin is Bryan, 1984; Crane, 1999; Granum and Lund, 1997). The foods
normally trypsin sensitive, but people with low intakes of associated with the two types somewhat reflect the geographic
protein or who consume trypsin-inactivating foods (eg, sweet distribution of the types, as the emetic type predominates in
potatoes) are more at risk than carnivorous people with normal Japan, while in North America and Europe, the diarrhea type is
trypsin levels (Granum and Brynestad, 1999; Granum, 2006). most often seen.
CPE is enterotoxic and follows an ordered series of events, first Evidence is accumulating that other species of Bacillus may
causing cellular ion permeability, followed by macromolecular elaborate food toxins, including Bacillus thurigensis, B.
(DNA, RNA) synthesis inhibition, morphologic alteration, cell subtilis, B. licheniformis, and B. pumilis (Crane, 1999; Granum
and Baird- Parker, 2000; Granum, 2006).
viscera, following which is a cascade of inflammatory mediator
release. All the SE toxins share a number of properties: an ability to
cause emesis and gastroenteritis in primates, superantigenicity,
Staphylococcus aureus Staphylococcal intoxication includes intermediate resistance to heat and pepsin digestion, and tertiary
staphyloenterotoxicosis and staphylococcus food poisoning. S. aureus structural similarity, including an intramolecular disulfide bond.
produces a wide variety of exoproteins, including toxic shock Induction of emesis separates the SE toxins from TSST-1, but the
syndrome toxin-1 (TSST-1), the exfoliative toxins ETA and ETB, induction of emesis is not directly correlated to superantigen activity
leukociden and the staphylococcal enterotoxins (SEA, SEB, SECn,19 (Granum, 2006). The exact link between superantigenicity and lethality
SED, SEE, SEG, SHE, and SEI). TSST-1 and the staphylococcal by the SE toxins and TSST-1 is not known, but may be dependent upon
enterotoxins (SE) are also known as pyrogenic toxin su- perantigens cytotoxicity for certain cells, possibly in the kidneys, liver, or vascular
(PTSAgs) on the basis of their biological characteristics. There is a endothelium (Monday and Bohach, 1999). Sources of Staphylococcus
relatively wide degree of molecular diversity among SE toxins and this include nose and throat discharges, hands and skin, infected cuts,
is thought to be the result of adaptation to allow for a broad range of wounds, burns, boils, pimples, acne, and feces. The anterior nares of
potential hosts (Monday and Bohach, 1999). Some, but not all, SE humans are the primary reservoirs. Other reservoirs include mastitic
require Zn++for superantigen activity. Although enterotoxemia only udders of cows and ewes (responsible for contamination of
develops from ingestion of large amounts of SE, emesis is produced as unpasteurized milk); and arthritic and bruised tissues of poultry. Foods
the result of stimulation of the putative SE receptors in the abdominal usually are contaminated after cooking by persons cutting, slicing,
chopping, or otherwise handling them and then keeping them at room reported that year were from organically grown lettuce, although
temperature for several hours or storing them in large containers. organic foods apparently account for less than 1% of the total food
Foods associated with staphylococcal poisoning include cooked ham;
supply.At the basis of the potential problem is the use of
meat products, including poultry and dressing; sauces and gravy;
cream- filled pastry; potatoes; ham; poultry; fish salads; milk; cheese; inadequately treated manure for fertilizer. Human cases of E. coli
bread pudding; and generally high protein leftover foods (Cohen, 1972;
O157:H7 infec- tion have been reported from consumption of
Bryan, 1976, 1984; Minor and Marth, 1976; Crane, 1999; Dinges et al.,
contaminated lettuce, potatoes, radish sprouts, alfalfa sprouts,
2000).
cantaloupe, and unpasteurized apple cider and juice (Karch et al.,
1999). Adequate treatment of manure requires composting the manure
Escherichia coli Although E. coli does not produce a pre-formed toxin, for a minimum of 3 months during which, the heap must reach a
it deserves mention because of the overwhelming publicity the temperature of 60◦C and although this may be adequate to kill
emergent strain O157:H7 has received (H and O refer to flagellar vegetative pathogens, it will not destroy spore-formers such as
antigens and virulence markers). There are four categories of E. coli Clostridium perfringens or C. botulinum. Survival of viruses and
associated with diarrheal disease: enteropathogenic (EPEC), en- protozoa during composting is not known (Anonymous, 1999).
terotoxigenic (ETEC), enteroinvasive (EIEC), and Vero cytotoxin-
producing E. coli (VTEC). The classification VTEC also includes
Bovine Spongiform Encephalopathy
“shiga-like toxin”-producing E. coli (or SLTEC) and “shiga toxin”-
producingE. coli(STEC). EnterohemorrhagicE. coli(EHEC) refers to Bovine spongiform encephalopathy (BSE) was first identified in Great
those strains producing bloody diarrhea and are a subset of VTEC. The Britain in 1986. BSE is a neurological disease classified as a
reference to shiga toxin is the result of the clinical similarity of the transmissible spongiform encephalopathy (TSE) and is similar to TSEs
bloody diarrhea caused by EHEC to that caused by Shigellae. Each of in other species including scrapie (sheep and goats), transmissible
the diseases presented by the four categories is also associated with mink encephalopathy (ranch-bred mink), chronic wasting disease
one or more toxins (Willshaw et al., 2000). (mule deer and elk), exotic ungulate encephalopathy (cap- tive exotic
Because cattle are a significant reservoir of E. coli, it is bovoids such as bison, orynx, kudu) and feline spongiform
logical that most outbreaks in the United States have been associated encephalopathy (domestic cats and zoo Felidae). TSEs among humans
with hamburgers and other beef products although raw vegetables include kuru, Creutzfeldt-Jakob Disease (CJD), and “new variant” CJD
(often (nvCJD) and Gerstmann–Str ä ussler–Scheinker syndrome (to be
distinguished from CJD by an earlier onset and tends to run in
families).
19 “n” indicating seven Clinically, all these diseases present neurological
deterioration and wasting, with the incubation period and interval from
subtypes.
clinical onset to inexorable death determined by the dose of infective
fertilized with manure) and unpasteurized apple cider and juice have
agent, its virulence and genetic makeup of the victim. The incubation
been reported as sources of outbreaks. Outbreaks in Europe are more
of BSE in cattle is generally 4–5 years (range of 20 months to 18 years)
often associated with contamination of recreational waters
and an interval of 1–12 months from presentation of clinical signs to
(swimming pools, lakes, etc.). Other sources of contamination include
death. Characteristic histologic lesions in the brain and spinal cord are
person-to-person contact (especially in families and among
vacuolation and “spongiform” changes. BSE fibrils (long strands of
institutionalized persons) and contact with farm animals especially
host glycoprotein called prion protein or PrP) in spinal cord
following educational farm visits (Karch et al., 1999).
preparations may be seen with electron microscopy following
The subject of organic food has increasingly captured the detergent extraction and proteinase K digestion. BSE/scrapie tissues
public interest. Within this issue, is a debate concerning the use of with highest infectivity are brain and spinal cord, followed by retina,
organic fertilizers (eg, cow manure) in organic and conventional spleen, tonsil lymph nodes, distal ileum, and proximal colon. The
farming, which may contain E. coli O157:H7 (Stephenson, 1997). Data infective agent can be transferred using preparations of neural tissue
reported to the US Centers for Disease Control and Preven- tion (CDC) from infected animals across species barriers. The most effective
in 1996, and tabulated in a CDC document entitled method of transfer is direct injection into the brain or spinal cord, but
“Clusters/Outbreaks of E. coli O157:H7 reported to CDC in 1996,” transfer has been reported with intraperitoneal injection and oral
show that approximately 10% of all E. coli O157:H7 infections
Table 30-26 Amounts of Heterocyclic Amines in Cooked Foods
AMOUNT (ng/g) IN COOKED FOOD
SAMPLE Iq MEIqX 4,8-DIMEIqX TRP-P-1 TRP-P-2

Broiled beef 0.19 2.11 0.21 0.25 Fried ground beef 0.70 0.64 0.12 0.19 0.21 Broiled chicken 2.33 0.81 0.12 0.18 Broiled mutton 1.01 0.67 0.15 Food-grade be
SOURCES: Sugimura T, Wakabayashi K, Nagao M, et al.: Heterocyclic amines in cooked food, in Taylor SL, Scanlan RA (eds.): Food Toxicology: A
Perspective on the Relative Risks. New York, Marcel Dekker, 1989, p. 45. With permission from Copyright Clearance Center. Adamson RH: Mutagens and carcinogens formed during cooking of foods and m
formation. Cancer Prevention Vol 1(November):
1–7 (1990). With permission from Lippincott Williams &Wilkins. IQ = 2-amino-3-methylimidazo[4,5-f]quinoline; MeIQx = 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline; 4,8-DiMeIQx = 2-amino-3,4,8-tr
f]quinoxaline; Trp-P-1 = 3-amino-1,4-dimethyl-5h-pyrido[4,3-b]indole; Trp-P-2 = 3-amino-1-methyl-5h-pyrido[4,3-b]indole.
Collee, 2000). Likewise, hemophilic patients have not
reflected an
dosing. Vertical transfer (mother to offspring) has been increased incidence of nvCJD, although CJD transmission has
reported among domestic cattle and lateral transfer through been documented as the result of injections of human growth
biting or injury (especially among mink) has also been reported. hormone or gonadotrophin (derived from human pituitary
Indirect transmission of chronic wasting disease (CWD) has gland), implantation of dura mater and corneas and even
been reported recently (Miller et al., 2004); CWD of mule deer infected EEG electrodes and neurosurgical instruments
(Odocoileus hemionus) can be transmitted from environments (Prusiner, 1994; Lee et al., 1998; Collee, 2000).
contaminated by excreta 2.2 years earlier or decomposed
carcasses ∼1.8 years earlier. Substances Produced by Cooking
It is generally agreed that the infective agent is likely a variant
of scrapie (endemic to sheep) and was transferred to cattle from Heterocyclic Amines Tolerances cannot be set for
rendered sheep via inadequately processed meat and bone contaminants that are produced as a result of an action taken
meal protein supplement. There is strong evidence and general by the consumer. An example of this type of contaminant is
agreement that the outbreak was amplified and spread heterocyclic amines, which are generated during cooking.
throughout the UK cattle industry by feeding rendered Heterocyclic amines (HCAs) were discovered serendipitously
(contaminated) bovine meat- and-bone meal to young calves. by Japanese investigators who, while examining the
Disputes have arisen about other details of BSE and its mutagenicity of smoke generated by charred foods, found that
relationship to other TSEs and effects in man because of an the extracts of the charred surfaces of the meat and fish were
expectation of conformation by BSE to historical principles of quantitatively more mutagenic than could be accounted for by
disease transmission. Based on the BSE controversy, the FDA the presence of polycyclic aromatic hydrocarbons (Sugimura
has published a proposed rule (Federal Register 70:58569- et al., 1989). Collectively, there are more than 20 HCAs. They
58601, 2005), which lists so-called high-risk tissues not are formed as a result of high-temperature cooking of proteins
allowed in animal or pet food due to potential BSE risk to (especially those containing high levels of creatinine) and
livestock or pets and ultimately, humans. carbohydrates. Normally, as a result of such heating, desirable
The currently most accepted theory is that the infective agent flavor components are formed, for example, pyrazines,
is a modified form of a normal cell surface component known pyridines, and thiazoles. Intermediates in the formation of
as prion protein PrPc (alpha-helix form), which when these substances are dihydropyrazines and dihy- dropyridines,
which in the presence of oxygen form the flavor com-
introduced into an organism causes a conversion of PrPc into
ponents; however, in the presence of creatinine, HCAs are
a likeness of itself (ie, the isoform), but then designated as the
formed (Table 30-26) (Chen and Chiu, 1998; Schut and
pathogenic form, PrP* or PrPsc for scrapie; or PrPres for
Snyderwine, 1999). These substances are rapidly absorbed by
protease resistant (beta-pleated sheet form) (Flechsig and
the GI tract, are distributed to all organs, and decline to
Wissmann, 2004; Frosch et al., 2005). The agent does not
undetectable levels within 72 hours. HCAs behave as
possess nucleic acid. The pathogenic form of the protein,
electrophilic carcinogens (Table 30-27). They are metabolized
PrP*, is both less soluble and more resistant to enzyme
first by N-hydroxylation followed by further activation by O-
degradation than the normal form. The protein is resistant to
acetylation or O-sulfonation to react with DNA. DNA adducts
heat, antimicrobials, ultraviolet or ionizing radiation, and is
are formed with guanosine in various organs, including the
not consistently inactivated with alcohol, formaldehyde,
liver, heart, kidney, colon, small intestine, forestomach,
glutaraldehyde, or sodium hydroxide. Phe- nol and sodium
pancreas, and lung. Unreacted substances are subject to phase
hypochlorite disinfection have had variable success.
II detoxication reactions and are excreted via the urine and
Investigators have concluded that the agent in nvCJD and BSE
feces. In vitro, HCAs require metabolic activation, with some
is the same strain and may be the same agent in feline
requiring O-acetyltransferase and others not. Although much
spongiform encephalopathy and exotic ungulate
of the mutagenicity testing has been carried out in TA98 and
encephalopathy. While this information might indicate a
TA100, these substances are mutagenic in mammalian cells
simple mode of transmission, workers with the highest
both in vitro and in vivo, Drosophila, and other strains of
potential incidence of exposure to BSE or TSE (sheep farmers,
Salmonella (Munro et al., 1993; Skog et al., 1998; Sugimura
butchers, veterinarians, cooks, and abattoir workers) do not
and Wakahayashi, 1999).
have an unusually high incidence of nvCJD (Prusiner, 1991;
Table 30-27 Mutagenicity and Carcinogenicity of Heterocyclic Amines
NUMBER OF REVERTANTS u/g CARCINOGENICITY HCA (STRAIN TA98) SPECIES STATISTICALLY SIGNIfiCANT
TUMORS
MeIQ 47,000,000 Mouse Liver, forestomach

Rat Zymbal gland, oral cavity, colon, skin, mammary gland IQ 898,000 Mouse Liver, forestomach, lung
Rat Liver, mammary gland, Zymbal gland Monkey Liver, metastasis to lungs MeIQx 417,000 Mouse Liver, lung, lymphoma, leukemia
Rat Liver, Zymbal gland, clitoral gland, skin Glu-P-1 183,000 Mouse Liver, blood vessels
Rat Liver, small and large intestine, brain, clitoral gland,
Zymbal gland DiMeIQx 126,000 No data Trp-P-2 92,700
Mouse Liver, lung
Rat Liver, clitoral gland Trp-P-1 8,990 Mouse Liver
Rat Liver, metastasis to lungs PhIP 1,800 Mouse Liver, lung, lymphoma
Rat Colon, mammary gland Glu-P-2 930 Mouse Liver, blood vessels
Rat Liver, small and large intestine, Zymbal gland, brain,
clitoral gland
SOURCE: Adapted from Sugimura T, Wakabayashi K, Naga o M, et al.: Heterocyclic amines in cooked food, in Taylor SL, Scanlan RA (eds.): Food Toxicology: A Perspective on the Relative Ri
Marcel Dekker, 1989, pp. 36–43. With permission from Copyright Clearance Center. MeIQ = 2-amino-3,4-dimethylimidazo[4,5-f]quinoline; IQ = 2-amino-3-methylimidazo[4,5-f]quinoline; MeIQx
dimethylimidazo[4,5-f]quinoxaline; Glu-P-1 = 2-amino-6-methyldipyrido[1,2-a:3 ,2 -d]imidazole; 4,8-DiMeIQx = 2-amino-3,4,8-trimethyl-3H- imidazo[4,8-f]quinoxaline; Trp-P-1 = 3-amino
5h−pyrido[4,3-b]indole; Trp-P-2 = 3-amino-1-methyl-5h−pyrido[4,3-b]indole; PhIP = 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine; glu-p-2 = 2-aminodipyrido[1,2-a:3 ,2 -d]imidazole.
Acrylamide is formed in foods that are high in carbohydrate, but low
in protein, which are subjected to processing temperatures of at least
Acrylamide Prior to 2002, when Swedish investigators detected 120◦C. These high-temperature processing conditions are largely the
acrylamide in food (Table 30-28), it was of interest only to special- ists same as required for the Maillard reaction which imparts a toasted, or
in worker safety, as this chemical is an important intermediate in the baked (ie, “crust”) flavor to breads, toast, and other baked goods and,
manufacture of polyacrylamides. Although there are many industrial breaded meats and vegetables for saut é ing or frying and, most
and manufacturing uses of polyacrylamides, the bulk of production are critical in production of French fries and potato chips. Most
used as chemical flocculants for water treatment, oil recovery and, in acrylamide is formed in the final stages of baking, grilling, or frying
construction of dam foundations, tunnels and sewers—consumer as the moisture content of the food falls and the surface temperature
exposure is largely incidental (NTP, 2004b). End users are exposed to rises (JECFA, 2005). The presence of ammonium bicar- bonate as a
polyacrylamide, which is not toxic as long as the monomer is not leavening agent increases the formation of acrylamide. A critical
present. Acrylamide (the monomer) was known to be a neurotoxin, element is the presence of asparagine, and amino acids competing
creating morphological changes in peripheral nerves at doses as low with asparagine in the Maillard reaction, which reduce the levels of
as 1 mg/kg BW/d. Much more is now known about acrylamide and its acrylamide in the final product. Strategies for mitigation focus on
primary metabolite, glycidamide, which is produced from acrylamide reduction of asparagine through use of asparagi- nase, breeding and
by the enzyme CYP2E1; both acrylamide and glycidamide will form selection of low asparagine plants and prolonged yeast fermentation;
adducts with hemoglobin. Acrylamide is absorbed rapidly and alternatively, processing temperature could be lowered (JECFA,
extensively (23–48% of the administered dose to rodents) from the 2005).
gastrointestinal tract. Both acrylamide and glycidamide are largely Acrylamide intake estimates range from 0.3 to 2.0μg/kg
eliminated as mercapturic acid conjugates. Repeated dosing of BW/d for the average population, with the 90th to 97th percentile at 0.6
acrylamide (in drinking water at 21 mg/kg BW/d for 40 days) produces to 3.5 μg/kg BW/d at the 99th percentile at 5.1 μg/kg BW/d. Primary
morphological changes in the brain areas critical for learning, memory, sources include French fries (1–30%), potato chips (6–46%), coffee
and other cogni- tive functions (ie, cerebral cortex, thalamus, and (13–39%), pastry and cookies (10–20%), and bread and rolls/toasts
hippocampus) (JECFA, 2005). Acrylamide was classified as “probably (10–30%). The national average and “high intake users” are 1 and 4
carcinogenic to humans” (IARC Group 2A) by the International μg/kg BW/d, respectively. The NOEL for morphological change in
Agency for Research on Cancer (IARC, 1994) and “reasonably nerves and for reproductive effects is 200 and 2000 μg/kg BW/d,
anticipated to be a human carcinogen” by the National Toxicology respectively (JECFA, 2005).
Program (NTP, 2004b).
Table 30-28 Representative Concentrations of Acrylamide in Several Foods

MEAN CONC. REPORTED MAXIMUM FOOD (μg/kg) (μg/kg)
Cereal-based products
Breads and rolls 446 3436 Pastry and cookies 350 7834 Breakfast cereals 96 13
Baked potato 169 1270 Potato chips 752 4080 French f
Coffee, brewed, ready to drink 13 116 Coffee extracts 1100 4948 Coffee, decaffeinated 668 5399 Coffee substitutes 8
Raw, boiled and canned 4.2 25 Processed (toasted, baked, fried, grilled) 59 202 Infant formula <5 15 Baby food
JECFA (2006) Evaluation of Certain Food Additives and Contaminants. Sixty-fourth report of the Joint FAO/WHO Expert Committee on Food Additives (JECFA). WHO Technical Report Series 930. World H
Geneva, pp. 20–21. (http://whqlibdoc.who.int/trs/WHO TRS 930 eng.pdf) (accessed on 17 May 2007).
Other contaminations include contamination of milk with
pyrrolizidine and other alkaloids after a cow has fed on tansy
Miscellaneous Contaminants in Food rag- wort (Senecio jacobaea) and tremetol contamination of
milk from white snakeroot (Eupatorium rugusum).
Sometimes the items under the miscellaneous heading are the
most interesting. For example, Rodricks and Pohland (1981)
pointed out an interesting historical case of the possible transfer
of a toxic botanic chemical from an animal to humans, which
CONCLUSION
was first identified by Hall (1979). It is found in the Bible,
Food toxicology differs in many respects from other
Book of Numbers, 11:31–33, which describes hungry Israelites
subspecialties of toxicology largely because of the nature and
inundated with quail blown in from the sea; those who ate the
chemical complex- ity of food. Food consists of hundreds of
quail quickly died. Hall speculated that the quail had consumed
thousands of chemical substances in addition to the macro- and
various poisonous berries, including hemlock, while they
micronutrients that are essential to life. The federal law
overwintered in Africa. The hemlock berry contains coniine,
defining food safety in the United States, the FD&C Act,
a neurotoxic alkaloid to which quail are resistant and which can
provides a scheme for establishing the safety of foods, food
accumulate in their tissue. Humans are not resistant to coniine,
ingredients, and contaminants. Whereas the act does not specify
and consumption of large quantities of quail tissue containing
how the safety of food and its components and ingredients is
the neurotoxin could result in death as described in the biblical
to be demonstrated, it emphasizes the need for reasonable
text.
approaches in both the application of tests and their interpreta-
Mountain laurel, rhododendron, and azaleas all possess an- tion. New policies, consistent with the safety provisions of the
dromedotoxin (now called acetylandromedol) and Act, are being developed to provide guidance for determination
grayanotoxins (I, II, and II) in their shoots, leaves, twigs, and of the safety-in-use of novel foods and those foods derived from
flowers. Honey made from flowers of these plants is toxic to new plant varieties.
humans, and after an asymptomatic period of 4–6 hours,
Contaminants found in food may be divided into two large
salivation, malaise, vomiting, diarrhea, tingling of the skin,
classes: those that are unavoidable by current good
muscular weakness, headache, visual difficulties, coma, and
manufacturing practice and those that are not. The former class
convulsions occur. Life-threatening bradycar- dia and arterial
is represented by substances such as certain chlorinated organic
hypotension may occur. Needless to say, beekeepers maintain
compounds, heavy metals, and mycotoxins which have been
apiaries well away from these species of plants. A similar
determined to be unavoidable by current food-manufacturing
poisoning occurs with oleander (Nerium oleander and N.
practice and for which tolerances or action levels may be
indicum), where honey made from the flowers, meat roasted on
established. Additionally, pesticide residues and residues of
oleander sticks, or milk from a cow that eats the foliage can
drugs used in food-producing animals may have tolerances
produce prostrating symptoms. The oleander toxin consists of a
established when necessary to protect public health. For
series of cardiac glycosides: thevetin, convallarin, steroidal,
avoidable class of contaminants, tolerances are not set either be-
helleborein, ouabain, and digitoxin. Sympathetic nerves are
cause public health concerns dictates that the mere presence of
paralyzed; the cardiotoxin stim- ulates the heart muscles similar
the substance or agent demands immediate regulatory action or
to the action of digitalis, and gastric distress ensues (Anderson
because
and Sogn, 1984; VonMalottki and Weichmann, 1996).
borne illnesses in developed countries is attributable to
microbiological
contamination of food arising from the pathogenicity and/or tox-
contamination results from food preparation in the home, which is igenicity of the contaminating organism. Thus, the overwhelming
beyond FDA control. concern for food safety in the United States remains directed toward
It is important to emphasize that the vast majority of food- preserving the microbiological integrity of food.
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BAB 30

Frank N. Kotsonis dan George A. Burdock

TOLERANSI SETTING UNTUK SUBSTANCES DALAM

Tabel 30-6 Bahan Tambahan Makanan Langsung Menurut Fungsi

NUMBERURAIAN URAIAN Contoh

(8) Pengemulsi dan garam pengemulsi Zat yang mengubah

pemrosesandan kualitas makanan jadi

Table 30-6 (Continued)

NUMBER DESIGNATION DESCRIPTION EXAMPLES

(15) Fumigants Volatile substances used for controlling insects

(23) pH control agents Substances added to change or maintain active

Table 30-6 (Continued)

NUMBER DESIGNATION DESCRIPTION EXAMPLES

(26) Sequestrants Substances that combine with

FD&C Blue No.1 5.0% rats 363 1.23

Table 30-10 Databases for Estimating Food Intake

Continuing Survey of Food Intakes by Individuals, USDA, 1985,

4 Thisis the source of the 100 safety factor.

cumulative estimated daily intake (CEDI), the following equation is used:

Table 30-12 Examples of GRAS Substances and Their Functionality

CFR NUMBER SUBSTANCE FUNCTIONALITY

Degraded carrageenan is classified by the International Agency for Assessment of Carcinogens

Carcinogenic Contaminants The Delaney clause, which

Table 30-16 Symptoms of IgE-Mediated Food Allergies

FOOD ALLERGIC PROTEINS

Table 30-19 Anaphylactoid Reactions to Food

FOOD REACTION MECHANISM REFERENCE

(EPA) and is accomplished under both FIFRA and the FD&C

Table 30-22 Examples of Levels of Chlorinated Hydrocarbons in British Food

CHLORINATED HYDROCARBONS μg/kg

Table 30-23 Sources of Dietary NOCs

consumption of H2-receptor blockers or antacids decreases

Table 30-24 Nitrate and Nitrite Content of Food

Table 30-26 Amounts of Heterocyclic Amines in Cooked Foods

AMOUNT (ng/g) IN COOKED FOOD

SAMPLE Iq MEIqX 4,8-DIMEIqX TRP-P-1 TRP-P-2

MeIQ 47,000,000 Mouse Liver, forestomach

Table 30-28 Representative Concentrations of Acrylamide in Several Foods

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