© FSANZ 2002

© FSANZ 2002 FUNCTIONS OF FSANZ  FSANZ is a partnership between the Australian Commonwealth, State and Territory and New Zealand governments - an independent, expert body.  Responsible for developing, varying and reviewing standards for food available in Australia and New Zealand and for a range of other functions including coordinating national food surveillance systems, assessing policies about imported food and developing codes of practice with industry.

© FSANZ 2002 Toxicology of acrylamide Dr Paul Brent/Dr Glenn Stanley FSANZ MARCH 2003

© FSANZ 2002 Acrylamide FSANZ is currently undertaking a review of the toxicology of acrylamide: 1.To determine whether acrylamide is a possible human carcinogen 2.To ascertain levels of acrylamide in food in Australia and New Zealand 3.If possible to establish a threshold for carcinogenicity 4.To establish risk management options for regulation of acrylamide in food if necessary

© FSANZ 2002 Acrylamide Toxicological studies available: Absorption, distribution, metabolism, excretion Acute and repeat dose Mutagenicity/genotoxicity Developmental and reproductive toxicity Carcinogenicity Epidemiological (human)

© FSANZ 2002 Toxicological profile ( Absorption, distribution, metabolism, excretion) Animals-Incomplete information available Rapid and complete absorption by oral, inhalation and dermal routes in a range of species Rapid distribution to a range of tissues and organs Accumulation in liver, kidney, testes, epididymis, skin and red blood cells Metabolised to glycidamide 60% dose excreted in urine in 24 h Information on bioavailability from foods as consumed needed

© FSANZ 2002 Toxicological profile ( Absorption, distribution, metabolism, excretion) Humans Limited information-mainly from accidental exposure Rapid and extensive absorption by oral route Haemoglobin adducts in blood samples via inhalation and dermal routes

© FSANZ 2002 Acute and repeat dose studies Oral LD 50 in rats, mice, guinea pigs and rabbits mg/kg bw Skin and eye irritant and skin sensitization Main effect non-lethal reversible neurotoxicity (peripheral nerves) Humans-acute poisoning at 375 mg/kg leading to hepatic effects and peripheral neuropathy PNS and CNS effects following repeated exposure in animals and humans. NOAELs and LOAELs established for animals from repeat-dose studies but difficult to characterise for humans

© FSANZ 2002 Developmental and reproduction studies Resorptions, decreased birth weights and bodyweight gain, decreased litter size, tibial and optic nerve degeneration in neonates. Parental effects-ataxia, abnormal gait, peripheral neuropathy, decreased litters/dam, increased pre- implantation loss, degeneration testicular epithelia, increased incidence sperm head abnormalities. A review of the available developmental toxicity data suggested that the LOEL was 20 mg/kg bw/day; no NOAEL could be established (Dearfield, 1998).

© FSANZ 2002 Genotoxicity In vitro Gene mutation assays-negative in bacterial assays (Ames test); however, metabolite glycidamide +ve; Mammalian and DNA tests generally negative or equivocal (CHO and mouse lymphoma cells-equivocal) but some positive (mouse lymphoma). Mutations in post-meiotic stages spermatogenesis. Chromosomal assays-aberrations and mitotic disruption in mammalian cell (in vitro CHO cells and lines), polyploidy and spindle disturbances. UDS negative for rat hepatocytes and +ve for human mammary cultures.

© FSANZ 2002 Genotoxicity In vivo Aberrations in bone marrow, spermatocytes, peripheral blood reticulocytes, spleen lymphocytes and spermatids UDS in rat and mouse spermatocytes +ve Dominant lethal +ve

© FSANZ 2002 Carcinogenicity Johnson et al (1986) 2-year study Fischer (F-344) rats receiving 0, 0.01, 0.1, 0.5 or 2 mg/kg bw/day. At doses of 2.0 mg/kg bw/day statistically increased incidences of mostly benign tumours of the mammary gland (fibroademonas), thyroid gland [1](adenomas), oral tissue (papilomas), clitoral gland (adenomas), pituitary gland (adenomas) and uterus (adenocarcinomas) in females. A non-statistical increase in incidence of CNS tumours (astrocytomas of the brain and spinal cord) were also reported in male and female rats at high dose. Statistically significant incidences of testicular mesotheliomas, at doses of 0.5 or 2.0 mg/kg bw/day and adrenal pheochromocytomas and thyroid adenomas in males at 2 mg/kg bw/day only) were observed. [1] Not statistically significant in females[1]

© FSANZ 2002 Carcinogenicity (Continued) Friedman et al (1995)-male and female F-344 rats received doses of approximately 0, 0.1, 0.5 or 2.0 mg/kg bw/day and 0, 1.0 or 3.0 mg/kg bw/day acrylamide in drinking water, respectively. Study did not repeat some of the tumours noted in the earlier study (Johnson et al., 1986) (CNS glial neoplasms, papillomas of the oral cavity, adenomas of the clitoral gland, and uterine adenocarcinomas) at a similar dose range and in an identical rat species, although it did confirm mesotheliomas of the testis and benign tumours of the mammary and thyroid glands.

© FSANZ 2002 FSANZ evaluation of results of both carcinogenicity studies Mammary gland fibroadenomas incidence 28 to 38% at high dose (2-3 mg/kg bw/day) compared to historical control range of 2-44%; Testicular mesotheliomas incidence 16-18% compared to historical control range of 2-6% at high dose (2 mg/kg bw/day); Thyroid adenoma incidence 12-16% in males and 16% in females compared to historical control range of 0-5% males and 0-4% females at high dose (2-3 mg/kg bw/day); Uterine adenocarcinoma incidence of 8% at 2 mg/kg bw/day compared to historical control range of 0-2.5%. Adrenal pheochromocytoma incidences of 17% in males at 2 mg/kg bw/day compared to historical control range 1-14%.

© FSANZ 2002 Carcinogenicity (humans) 3 cohort studies (Sobel et al 1986; Collins et al, 1989; Marsh et al 1999) over years demonstrated no epidemiological evidence of a causal relationship between exposure to acrylamide and mortality Recent study (Mucci et al, 2003) assessed the diets of 987 cancer patients (591 with cancer of the large bowel, 263 with bladder and 133 with kidney cancer) and compared to 538 healthy control individuals. Found lack of association between acrylamide and cancer in those subjects consuming moderate (  g/kg) or high levels (  g/kg) of acrylamide in 14 different food types.

© FSANZ 2002 Conclusions to date from FSANZ review Mechanism (s) of carcinogenicity unresolved Genotoxicity tests suggest that acrylamide is a genotoxic carcinogen in vivo Carcinogenicity assays in animals suggest increased tumour incidence primarily in hormonal tissues such as adrenal, thyroid, mammary gland, uterus and testes. Majority of tumours benign

© FSANZ 2002 Conclusions to date from FSANZ review Anomalies: Lack of a dose-response relationship and NO time-to tumour data available; Only 2 tumours of significance to humans: Testicular mesotheliomas[1] with an incidence level (16-18%) compared to historical control values for the Fischer rat strain (2-6%);[1] Uterine adenocarcinoma incidences were increased in high-dose groups (Johnson et al, 1986), appear to be uncommon lesions in F-344 rats, not found in Freidman et al (1995) study and histological basis for these tumours is unknown. [1] This appears as a rare tumour in humans but is quite common in the Fischer strain of rat. [1]

© FSANZ 2002 Conclusions to date from FSANZ review The lack of consistency in reported tumours suggests that further studies are still needed to be performed in a different rat strain or different species such as the mouse or dog to help elucidate the significance of the tumours reported in the two studies to date. The epidemiological cohort studies done in humans previously exposed to acrylamide and tracked over a prolonged period failed to demonstrate any evidence of acrylamide-induced tumorigenicity or carcinogenicity. Most recent epidemiological study should be interpreted with caution due to: (1) Swedish group selected may not represent populations in other countries; (2) Limited range tumours selected; (3) Case-control study may not have enough power to assess cause and effect compared to cohort studies.

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