Coughlin_IFT_NTP Acrylamide_June 14 2011


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Coughlin_IFT_NTP Acrylamide_June 14 2011

  1. 1. National Toxicology Program’s Acrylamide Bioassay:Risk Assessment Considerations James R. Coughlin, Ph.D. President, Coughlin & Associates Aliso Viejo, California SYMPOSIUM “The Long-awaited NTP Acrylamide Bioassay: Where Do We Go from Here?” Institute of Food Technologists Annual Meeting, New Orleans June 14, 2011 1
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  4. 4. Acrylamide Snapshot: Chemistry and Toxicology Occupational neurotoxin in humans; genotoxic & mutagenic in cell cultures Foods: mainly formed in the Maillard Browning Reaction from glucose or fructose and the common amino acid asparagine Known rat carcinogen, “probable human carcinogen” Metabolized to glycidamide, an epoxide animal carcinogen Protective enzymes can detoxify acrylamide and glycidamide Can chemically react with DNA to increase carcinogenic potential. 4
  5. 5. U.S. National Toxicology Program (NTP) Bioassayof Acrylamide [April 2011] FDA nominated acrylamide and glycidamide for complete toxicology testing in Nov. 13, 2002 letter: “…FDA requires a properly designed (dose response considerations and accounting for the food matrix through which humans are exposed), well-conducted, GLP-compliant bioassay. Results from such studies will provide the agency with sound scientific data by which more accurate risk assessments can be conducted.” 2-year cancer bioassay of acrylamide in rats and mice fed in drinking water (untreated control + 4 treatment doses), with many ancillary studies on metabolism, genotoxicity and toxicokinetics Draft Technical Report No. 575 released mid-Feb 2011 was peer-reviewed by the NTP Peer Review Panel on April 5. 5
  6. 6. NTP “Levels of Evidence” of Carcinogenic Activity CLEAR Evidence: “dose-related increase of neoplasms” SOME Evidence: “a chemical-related increased incidence of neoplasms” where the “strength of response is less than that required for clear evidence.” Also designated as “were also related” EQUIVOCAL Evidence: “a marginal increase of neoplasms that may be chemical related.” Also designated as “may have been related.” NO Evidence: “no chemical-related increases in malignant or benign neoplasms.” 6
  7. 7. Acrylamide Bioassay Conclusions: “Clear Evidence ofCarcinogenicity” in Male & Female Rats and Mice Male rats: “Clear” - malignant mesothelioma of epididymis & testes; malignant schwannoma of heart; benign adenoma / malignant carcinoma of thyroid “Some”- benign adenoma of pancreatic islets Female rats: “Clear” - benign fibroadenoma of mammary gland; benign papilloma of oral cavity; skin neoplasms; adenoma / carcinoma of thyroid “Some” - benign liver adenoma; clitoral gland malignant carcinoma “Equivocal” - malignant schwannoma of heart (“may have been related”) Male mice: “Clear” - benign adenoma of Harderian gland and lung; benign papilloma of forestomach; no increases in malignant tumors Female mice: “Clear” - benign adenoma of Harderian gland and lung; malignant carcinoma of mammary gland; benign neoplasms of ovary; malignant neoplasms of skin “Some” - benign papilloma of forestomach. 7
  8. 8. Formal Comments by Food and Chemical Industries Food Industry (GMA Coalition) – Coughlin, written and oral comments North American Polyelectrolyte Producers Association (NAPPA) – written comments only  Dr. Joseph Haseman (retired NTP Dir. of Statistics) provided his critique of many key tumor findings and factual errors;  Chairman twice referred to Haseman’s comments as “very detailed” but that “we can’t address them all”; in fact, they addressed none of the criticisms SNF / France (major acrylamide manufacturer) – written comments  Dr. Marvin Friedman (toxicology consultant) also presented oral comments; co-author of two previous acrylamide rat bioassays (1986, 1995) NTP Peer Review Panel – I believe a very cursory review; did not address or modify conclusions based on industry comments. 8
  9. 9. Key Issues in Industry Comments Glycidamide: Draft Acrylamide TR should not be finalized until the Glycidamide TR is peer reviewed; Panel rejected this advice, even though Glycidamide’s results can help interpret acrylamide  Draft Acrylamide TR, page 33: “To test these hypotheses and to provide data for meaningful risk assessments, studies were conducted to compare the extent and types of tumors in B6C3F1 mice and F344/N rats treated chronically with either acrylamide or glycidamide.“ We learned that the Glycidamide Draft TR is delayed by 2 years, so at this time we are not going to get the benefit of this significant, expensive NTP bioassay to assist in acrylamide’s risk evaluation Maximum Tolerated Dose (MTD) was exceeded based on very poor animal survival over 2 years; some tumor findings may have been caused by excess acrylamide CNS toxicity rather than by acrylamide inherently acting as a carcinogen – but no discussion of this. 9
  10. 10. Key Issues in Industry Comments (cont’d) Historical Controls for tumors were poorly chosen, even though they are meant to be used to help interpret the current study; they give the % incidence of spontaneous tumors in untreated control animals over several years of testing in all NTP contract labs Most of the NCTR historical control data were 20-23 years old, while other NTP contract labs have done so many more recent studies; NCTR has no rat drinking water studies and only one mouse drinking water study in its database We argued that the more recent and extensive NTP historical control database (March 2010 at NTP’s website) is more appropriate to use NCTR’s Dr. Beland defended by simply claiming their controls have been “stable” since the beginning of their rat / mouse colony 30 years ago; but no such rat / mouse spontaneous tumor stability is known in decades of NTP historical controls (significant drifting upward has occurred). 10
  11. 11. Female Rat Mammary Fibroadenomas (Benign) Our Historical Controls argument is best illustrated here These benign tumors in acrylamide-dosed rats were unlikely to be caused by acrylamide, since even the top acrylamide dose produced less tumors (65%) than seen in the more recent NTP drinking water, untreated historical controls (74% + 12%); only the top acrylamide dose (65%) was statistically significantly increased over concurrent control (33%): % Tumor Incidence Acrylamide study concurrent controls: 33% NCTR historical controls: 35% (27.1 - 42.6%) Recent NTP “Oral/Dr. Water” controls: 74% + 12% Acrylamide (lowest to highest dose) 38% 52% 47% 65%* 11
  12. 12. Risk Assessment Considerations (Rat) JECFA used preliminary, non-peer reviewed NTP rat and mouse tumor data in their February 2010 evaluation and risk assessment of acrylamide (published March 2010) These NTP female rat benign mammary fibroadenoma tumors were used as the pivotal tumor endpoint in calculating the highest risk value based on rats We believe we demonstrated to NTP that all four acrylamide test doses produced mammary tumor incidences below the highest spontaneous background incidence of untreated NTP historical controls; in addition, this type of tumor occurs in rats but not in humans, and benign human tumors do not progress to malignancy JECFA should reevaluate acrylamide’s risk based on the lower incidences of malignant rat tumors relevant to humans. 12
  13. 13. Risk Assessment Considerations (Mouse) The NTP male mouse benign Harderian gland adenoma tumors were used by JECFA as the pivotal tumor endpoint in calculating the highest risk value based on mice or rats The Harderian gland is a tear-producing gland in the third eyelid of some mammals and rodents but is not found in humans; many toxicologists & pathologists believe that these tumors are not a scientifically justified endpoint for human risk assessment JECFA acknowledged this: “As humans have no equivalent organ, the significance of these benign mouse tumors in the Harderian gland is difficult to interpret with respect to humans. However, in view of acrylamide being a multisite carcinogen in rodents, the Committee was unable to discount the effect in the Harderian gland.” JECFA should reevaluate acrylamide’s risk based on the lower incidences of malignant mouse tumors relevant to humans. 13
  14. 14. Future Risk Assessment Considerations JECFA and other public health authorities should consider reevaluating the current acrylamide risk assessment after dismissing consideration of the NTP’s benign tumors in the rat mammary gland and mouse Harderian gland as not scientifically relevant to human risk assessment These two most sensitive tumor endpoints are not malignant tumors, and these tumor types are not relevant to humans JECFA and others should reevaluate acrylamide’s potential for human risk based on the lower incidences of relevant NTP malignant rat and mouse tumor endpoints I firmly believe that acrylamide is too important and widespread a contaminant in the human diet to have its risk determined by scientifically irrelevant rodent tumor endpoints. 14
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  17. 17. Proposition 65: Risk Assessment Reevaluation is Needed The current acrylamide No Significant Risk Level (NSRL) (set 1990):  NSRL = 0.2 µg/day  Based on the oral cancer potency estimate of 4.5 per mg/kg-d, derived by U.S. EPA using only the tumor results from the Johnson et al. (1986) rat chronic drinking water bioassay  Linearized multistage analysis of combined incidence data for all tumors in the CNS, mammary and thyroid glands, uterus and oral cavity in female F344 rats (no CNS or uterus tumors were increased in NTP rats) The NSRL should be reevaluated using state-of-the-art physiologically- based toxicokinetic (PB-TK) modeling:  NTP Bioassay results for rats and mice supersede the two old rat bioassays  Use rat and mouse tumors that are more relevant to humans  Use updated comparative metabolic and toxicokinetic data. 17
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  20. 20. For a Full Risk Evaluation, We Need More Focus on: Going beyond just counting tumors and modeling the results Acrylamide can also react with amino acids and proteins in the human body, which can keep it from subsequent reactions with critical DNA targets inside cells (see USDA Mendel Friedman’s key reviews):  Blood hemoglobin adducts are well-known biomarkers of exposure, but hemoglobin and other blood / organ proteins can be considered “sinks” for acrylamide, destroying the molecule  Dietary proteins may reduce acrylamide uptake during digestion in humans. 20
  21. 21. Food for Thought… Risk-Benefit Assessment ofAcrylamide-containing Foods 21
  22. 22. “Risk-Benefit” Assessment Considerations Interpretation of rodent cancer bioassays of extreme chemical doses has often been shown to be overly conservative, especially if the Maximum Tolerated Dose may have been exceeded Assessing individual food chemicals has been our focus in the past, but we now need to consider the risks and benefits of whole foods using a “Holistic Approach” Failure to give proper weight to epidemiology studies showing little or no increased risk of foods containing the chemical, such as acrylamide Past failure to consider the POSITIVE health benefits of foods containing only trace levels of carcinogens  Cancer-protective substances:  nutrients like fiber and vitamins  antioxidants  inducers of detoxification enzymes. 22
  23. 23. General Scheme of Maillard Browning Reaction Ammonia Melanoidins Alkyl amines (pigments) Amine Amino acids Proteins HEAT Phospholipids Amino-Carbonyl Volatile Compounds Interaction (aroma chemicals) (Amadori Products) Aldehydes Ketones CarbonylsCarbonyl Sugars Esters Furans Oxazoles Amides (Acrylamide) Carbohydrates Pyrroles Imidazoles Lipids Thiophenes Pyridines Heterocyclic Compounds Thiazoles Pyrazines 23
  24. 24. “Maillard Browning Reaction” – Possible Beneficial Health Effects Flavors, aromas, colors and texture of browned foods depend on the Maillard Browning Reaction, but carcinogens are also formed However, Antioxidants (AOX) produced by Maillard Reaction may protect against diseases linked to oxidative damage (cancer, diabetes, atherosclerosis, arthritis, inflammation, etc.) Specific Maillard Reaction Products (MRPs), including the brown melanoidin polymers (they are polyphenolic AOX) and heterocyclic flavor compounds, are known to have antioxidant, anti-carcinogenic and anti-mutagenic effects Some MRPs also induce protective detoxification enzymes, including the acrylamide detoxification enzyme, glutathione-S-transferase (GST). 24
  25. 25. Does Acrylamide in Food Pose a Real Riskto Human Health? Risk characterization traditionally includes:  Rodent cancer bioassay results (like the NTP bioassay)  Biomarker and metabolic studies in animals and humans  Reliable data on human intake estimates But for acrylamide in heated foods, we must consider…  Bioavailability may be less in human diets than in water  Consideration of thresholds for some of the NTP tumors and non-linear dose modeling; hormonal mechanisms?  Dietary epidemiology studies generally support lack of significant risk globally  Consideration of health-protective, beneficial components of acrylamide-containing foods. 25
  26. 26. Thank You! 26