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Chemical Hazards: How Do We
Translate Presence to Risk?
An Overview of Risk Analysis
James R. Coughlin, PhD CFS
President,...
Objectives/Outline
 Why is toxicology and risk assessment of
chemicals important for foods and food
ingredients?
 Genera...
Paracelsus (1493-1541)
THE basic
tenet of all
Toxicology:
“The dose
alone
makes the
poison.”
Toxicology – A Multidisciplinary Science
 Chemistry
 Biology
 Pathology
 Physiology
 New Fields:
 Genomics
 Proteom...
Acute / Chronic Exposure and
Health Effects
 “Acute” Exposure
A single exposure to a chemical that can result
in some for...
Factors That Influence Toxicity
 Dose / duration / frequency of intake
 Species / strain / age / sex
 General state of ...
Fate of Toxicants in Living Systems
“ADME”
 Absorption - how much is absorbed by the body?
 Distribution - what organs/b...
Specialized Toxicity Tests
1. Reproductive (multigeneration)
2. Teratogenicity (birth & developmental)
3. Mutagenicity (sh...
Human Relevance of Rodent Cancer Bioassays
 Some eminent toxicologists have questioned the human relevance
of tumors seen...
Risk Assessment Paradigm
 Hazard Identification - Determination of adverse effects
caused by high intakes of the chemical...
Methods for Oral “RfDs”
 RfDs - U.S. EPA’s Reference Dose (similar to other agencies’
Acceptable Daily Intake or “ADI”)
...
13
14
Acrylamide Snapshot: Chemistry and Toxicology
 Occupational neurotoxin; genotoxic / mutagenic in cell cultures
 Known ra...
Swedish Discovery of Acrylamide in Foods
(announced April 2002)
Tareke et al., J. Agric. Food Chem. 50: 4998-5006 (2002)
...
Ammonia
Alkyl amines
Amino acids
Proteins
Phospholipids
Aldehydes
Ketones
Sugars
Carbohydrates
Lipids
Carbonyls
Esters
Ami...
Food Acrylamide Range (ppb)
Baby food/biscuits ND - 442
Breads/bakery products ND - 364
Cereals 11 - 1057
Chocolate produc...
Food Acrylamide Range (ppb)
French fries 117 - 1325
Fruits/vegetables (canned) ND - 83
Gravies/seasonings ND - 151
Infant ...
U.S. National Toxicology Program (NTP) –
Carcinogen Bioassay of Acrylamide
 U.S. FDA nominated acrylamide and glycidamide...
21
Acrylamide Risk Assessment Considerations Based
on NTP Cancer Bioassay
 FAO/WHO Joint Expert Committee on Food Additives ...
Recent Dietary Epidemiology Studies of
Acrylamide (Human Studies)
 Pelucchi et al. 2011. “Exposure to Acrylamide and
Huma...
“Acrylamide in Foods: A Review of the Science and
Future Considerations”
David R. Lineback, James R. Coughlin and Richard ...
No Significant Risk Level [NSRL] = (1 x 10-5)
Over 500 Carcinogens
MADL = No Observable Effect Level
1000
Over 300 Reprodu...
Acrylamide Battleground under California Prop 65
 Listed in 1990 as a carcinogen; “Safe Harbor” level = 0.2 μg/day; must
...
Benefit-Risk Evaluation –
The “Holistic Approach”
27
Food and Chemical Safety Issues
 We usually test individual food chemicals, not the whole
foods or beverages (except with...
30
“Benefit-Risk Evaluation” to Assess the Safety of
Foods Containing Toxicants and Carcinogens
I believe we’ve been doing i...
Coughlin_IAFP_Food chemical risk assessment_August 2013
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Coughlin_IAFP_Food chemical risk assessment_August 2013

  1. 1. Chemical Hazards: How Do We Translate Presence to Risk? An Overview of Risk Analysis James R. Coughlin, PhD CFS President, Coughlin & Associates Aliso Viejo, California jrcoughlin@cox.net www.linkedin.com/in/jamescoughlin IAFP / Charlotte / July 29, 2013 SYMPOSIUM “Chemical Risk Assessment 101: A Better Understanding of a Complex Subject Made Easier”
  2. 2. Objectives/Outline  Why is toxicology and risk assessment of chemicals important for foods and food ingredients?  General toxicology considerations, toxicity evaluation and risk assessment  Key determinants of human risk  Consider “Risk-Benefit” Evaluation:  Acrylamide as case example  California Proposition 65
  3. 3. Paracelsus (1493-1541) THE basic tenet of all Toxicology: “The dose alone makes the poison.”
  4. 4. Toxicology – A Multidisciplinary Science  Chemistry  Biology  Pathology  Physiology  New Fields:  Genomics  Proteomics  Toxicogenomics  Nutrigenomics  Nutrition  Immunology  Public Health  Pharmacology  Statistics  Epidemiology  Newest: The Microbiome
  5. 5. Acute / Chronic Exposure and Health Effects  “Acute” Exposure A single exposure to a chemical that can result in some form of toxicity or illness  “Chronic” Exposure Usually a lower-dose exposure for longer periods of time, associated with chronic/delayed effects
  6. 6. Factors That Influence Toxicity  Dose / duration / frequency of intake  Species / strain / age / sex  General state of health  Genetic & epigenetic factors  Nutritional status  Individual susceptibility (child, pregnant woman, elderly, immune compromised)  Synergism / antagonism  Adaptation to the effect
  7. 7. Fate of Toxicants in Living Systems “ADME”  Absorption - how much is absorbed by the body?  Distribution - what organs/body fluids does the toxicant go to?  Metabolism - is it modified by enzymes in the body, and to what extent? Activation to more toxic compound vs. Detoxification  Excretion - how much of the toxicant (or its metabolites) is retained and/or removed from the body?
  8. 8. Specialized Toxicity Tests 1. Reproductive (multigeneration) 2. Teratogenicity (birth & developmental) 3. Mutagenicity (short-term, in vitro & in vivo) 4. Neurobehavioral 5. Immuno-toxicological 6. Endocrine effects 7. Potentiation / Promotion 8. Carcinogen Bioassays
  9. 9. Human Relevance of Rodent Cancer Bioassays  Some eminent toxicologists have questioned the human relevance of tumors seen in lifetime rodent bioassays, and they believe it’s time to STOP doing chronic rodent bioassays at the “Maximum Tolerated Dose”  We toxicologists make two possibly flawed assumptions about chronic cancer bioassays…  Dose Extrapolation – effects seen at high rodent doses will also occur at much lower human doses  Species Extrapolation – if cancer is seen in rodents, then cancer probably occurs in humans  BUT…we need to understand Mechanisms and Modes of Action for a chemical before we can use bioassay tumor results for regulatory or warning purposes.
  10. 10. Risk Assessment Paradigm  Hazard Identification - Determination of adverse effects caused by high intakes of the chemical (epidemiology, clinical, animal, short-term and specialized studies)  Dose-Response Assessment  Selection of critical data set and toxic effect levels  Determination of Uncertainty or Safety Factors  Derive an Acceptable Daily Intake (ADI)  Exposure (Intake) Assessment  Evaluation of the range and distribution of human intakes  Risk Characterization  Estimation of the fraction of the population exceeding ADI  Evaluation of the magnitude of potential excess intakes.
  11. 11. Methods for Oral “RfDs”  RfDs - U.S. EPA’s Reference Dose (similar to other agencies’ Acceptable Daily Intake or “ADI”)  NOAEL - “No Observed Adverse Effect Level” – dose found experimentally where there is an absence of adverse effects  LOAEL - “Lowest Observed Adverse Effect Level” – the lowest experimental dose which increases the frequency or severity of toxic effects  Uncertainty Factors - in risk assessment of chemical toxicants, generally 10-fold increments with 100-fold as the default  Modifying Factors - magnitude depends on study weaknesses, severity of effects, bioavailability, susceptible subpopulations (such as diseased people, kids).
  12. 12. 13
  13. 13. 14
  14. 14. Acrylamide Snapshot: Chemistry and Toxicology  Occupational neurotoxin; genotoxic / mutagenic in cell cultures  Known rat carcinogen, classified as “probable human carcinogen”  Metabolized to glycidamide (an epoxide), also an animal carcinogen  Acrylamide & glycidamide can bind to DNA, amino acids and proteins  DNA adducts  carcinogenic potential  Blood hemoglobin adducts  biomarker of exposure  Dietary proteins may reduce acrylamide uptake in humans  Protective enzymes can detoxify acrylamide and glycidamide  Discovered by the Swedes in 2002 in hundreds of heat-processed food products, making up about 40% of our calories. 7
  15. 15. Swedish Discovery of Acrylamide in Foods (announced April 2002) Tareke et al., J. Agric. Food Chem. 50: 4998-5006 (2002)  Discovered after illness investigations of tunnel workers exposed to acrylamide as a grouting agent in 1997; background levels of Hemoglobin-acrylamide adducts of non- smoking Swedes were found to be elevated  Higher temperature / time / surface area increase levels:  Carbohydrate-rich foods high: 150 - 4,000 ppb  Protein-rich foods low, e.g. meats: 5 - 50 ppb  Not detected in unheated or boiled foods; 120 C is needed  Swedish adult acrylamide intake estimated to be 100 μg/day, but now known to be much lower in most populations. 16
  16. 16. Ammonia Alkyl amines Amino acids Proteins Phospholipids Aldehydes Ketones Sugars Carbohydrates Lipids Carbonyls Esters Amides (Acrylamide) Heterocyclic Compounds Amine Carbonyl Amino-Carbonyl Interaction (Amadori Products) HEATHEAT Furans Oxazoles Pyrroles Imidazoles Thiophenes Pyridines Thiazoles Pyrazines Melanoidins (pigments) Volatile Compounds (aroma chemicals) General Scheme of Maillard Browning Reaction
  17. 17. Food Acrylamide Range (ppb) Baby food/biscuits ND - 442 Breads/bakery products ND - 364 Cereals 11 - 1057 Chocolate products ND - 909 Coffee (roasted, not brewed) 37 - 374 Coffee (brewed) 5 - 11 Cookies/crackers 26 - 1540 Dairy drinks ND - 43 Dried foods/mixes ND - 1184
  18. 18. Food Acrylamide Range (ppb) French fries 117 - 1325 Fruits/vegetables (canned) ND - 83 Gravies/seasonings ND - 151 Infant formulas ND Nuts/nut butters ND - 457 Potato chips 117 - 4080 Snacks (other salty) 12 - 1340 Olives 123 - 1925 Prune juice 53 - 326
  19. 19. U.S. National Toxicology Program (NTP) – Carcinogen Bioassay of Acrylamide  U.S. FDA nominated acrylamide and glycidamide for complete toxicology testing in November 2002 for future risk assessment purposes  2-year cancer bioassay in rats and mice fed acrylamide in drinking water (untreated control + 4 treatment doses), with ancillary studies on metabolism, genotoxicity and toxicokinetics  NTP Technical Report No. 575 was peer-reviewed in April 2011; Panel accepted conclusions that there was “Clear Evidence of Carcinogenicity” in male & female rats and male & female mice  For consideration: the observed NTP tumor findings and cancer potencies may be useful in increasing acrylamide’s acceptable risk level. 14
  20. 20. 21
  21. 21. Acrylamide Risk Assessment Considerations Based on NTP Cancer Bioassay  FAO/WHO Joint Expert Committee on Food Additives (JECFA) acrylamide risk assessment (2010) used preliminary NTP data on benign tumors in the rat mammary gland and mouse Harderian gland, but these endpoints are not biologically relevant to human risk assessment  JECFA and national authorities should reevaluate acrylamide’s potential for human risk based on the lower incidences of more relevant NTP malignant rat and mouse tumor endpoints  Lack of human cancer risk must be factored into any risk assessment and risk management plans adopted by national regulatory agencies (FDA, Health Canada, EFSA) and global public health authorities (JECFA, Codex). 22
  22. 22. Recent Dietary Epidemiology Studies of Acrylamide (Human Studies)  Pelucchi et al. 2011. “Exposure to Acrylamide and Human Cancer - A Review and Meta-analysis of Epidemiologic Studies.” Annals Oncology 22: 1487-1499.  “Conclusions: Available studies consistently suggest a lack of an increased risk of most types of cancer from exposure to acrylamide.”  Lipworth et al. 2012. “Review of Epidemiologic Studies of Dietary Acrylamide Intake and the Risk of Cancer.” Eur. J. Cancer Protection 21: 375-386.  Concluded no increased human risk, and urged that no further epidemiology studies even be initiated. 23
  23. 23. “Acrylamide in Foods: A Review of the Science and Future Considerations” David R. Lineback, James R. Coughlin and Richard H. Stadler, Ann. Rev. Food Sci. & Technol. 3: 15-35 (April 2012)  Most countries have advised consumers to follow the dietary recommendations for a balanced diet issued by their food regulatory and public health agencies.  The data available to date have been insufficient to warrant any recommendation for a significant change in the dietary recommendations because of acrylamide.  Current epidemiological and toxicological evidence are insufficient to indicate that the amounts of acrylamide consumed in the normal diet are likely to result in adverse human health effects, particularly cancer. 24
  24. 24. No Significant Risk Level [NSRL] = (1 x 10-5) Over 500 Carcinogens MADL = No Observable Effect Level 1000 Over 300 Reproductive Toxicants [DARTs] Exposure (µg/day), Not Concentration!
  25. 25. Acrylamide Battleground under California Prop 65  Listed in 1990 as a carcinogen; “Safe Harbor” level = 0.2 μg/day; must stay below this level to avoid cancer warnings; if you can detect it, even a 1-ounce serving of any food exceeds this level  French fries: Attorney General sued and settled case (2008) against frozen fries/tater tots demanding a 50% reduction in levels; fast-food restaurant fries have had cancer warnings posted for years  Potato chips: AG settled (2008) the case against chip manufacturers; agreement to cut levels to 275 ppb by end of 2011 (20 - 85% reductions) to avoid warnings; no warnings currently being given  Cereals: Private “bounty hunter” lawyers sued cereal manufacturers in 2009; case is still pending  Coffee: “Bounty Hunter” sued coffee shops in 2010 over brewed coffee; 10 x 10-inch cancer warning placards have been posted; another case now in court against over 120 coffee roasters for packaged roast coffees. 26
  26. 26. Benefit-Risk Evaluation – The “Holistic Approach” 27
  27. 27. Food and Chemical Safety Issues  We usually test individual food chemicals, not the whole foods or beverages (except with epidemiology)  For whole foods, we must identify biologically active toxic component(s)  Must determine appropriate mechanism of action of specific chemicals (carcinogens, reproductive toxicants)  Key importance of dose-response relationships  Interactions with diet/nutrients, environment & drugs  Explore sensitive segments of population (young, aged)  Risk/Benefit Assessment is crucial need:  Goal: NO “significant or unreasonable” risk!!
  28. 28. 30
  29. 29. “Benefit-Risk Evaluation” to Assess the Safety of Foods Containing Toxicants and Carcinogens I believe we’ve been doing it the WRONG WAY for decades, by simply evaluating the risk of individual chemicals one by one in a food Going forward, I believe the RIGHT WAY is to evaluate the safety of the whole food by comparing its risks vs. benefits using the “Holistic Approach” Various “Benefit-Risk Evaluations” and regulatory guidance documents have recently been published in the U.S. [FDA’s “Mercury in Fish” evaluation] and Europe [EFSA, ILSI Europe]. 31

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