Upside-Down and Other Unusual Dose Responses and The Implications for Occupational Exposures

1. Upside-Down and Other Unusual Dose Responses and The Implications for Occupational Exposures Robert P. DeMott, Ph.D., DABT ENVIRON Internationalrdemott@environcorp.com AIHA – Florida Section Conference St. Augustine, Florida 28 September 2006

2. Goal and Approach • Provide background on derivation of toxicity-based exposure limits • Explain dose-response characteristics and regulatory simplifications • Introduce the growing recognition of “un-predicted” dose-response explanations for the complexities of real life.

3. Outline • Toxicology and dose-response basics • Thresholds and no-effect levels • Straight lines – good enough of gov’t work… • Non-linear low dose characteristics for cancer- hormesis • Dose-response complexities for individuals and chemical combinations

4. “Good Chemicals” and Hazardous Chemicals List A Arsenic Lead Trichloroethylene Mercury Warfarin (D-con rat bait) List B Oxygen Water Chromium (piccolinate) Vitamin A Digoxin

5. We Have an Intuitive Grasp of Hazard vs. Healthful… Which list do you associate with the scenes above?

6. Expected Associations List A Arsenic Lead Trichloroethylene Mercury Warfarin (D-con rat bait) List B Oxygen Water Chromium (piccolinate) Vitamin A Digoxin

7. Toxicological Reality • List A are all “medicines” Arsenic – Fowlers solution (1809-1950s) and other formulations • treat asthma, diabetes, malaria, syphilis Lead – various historical uses, folk remedies continue in use • for colic, menstrual disorders TCE • general anesthetic; orally, as treatment for worms

8. Mercury – Historically Significant, and … • Used to treat • Syphilis • Various GI upsets, skin conditions • historical experimentation lead to Paracelsus’ recognition: There are no substances which are not poisons, it is the dose that makes the poison

9. A Modern Example: Rat Poison or Heart Medication? Source: www.coumadin.com

10. Warfarin Common trade names: Athrombine-K; Brumolin; Compound 42; Coumadin; Coumafen; Coumarin; Coumefene; Dethmore; Dethnel; Eastern States Duocide; Fasco Fascrat Powder; Frass-Ratron; Kumader; Kumadu; Kypfarin; Maag Rattentod Cum; Mar-Frin; Maveran; Panwarfin; Prothromadin; Rat-a-way; Rat-b-gon; Rat-Gard; Rat-Kill; Rat-Mix; Rat-ola; Ratro; Rats-No-More; Rodafarin; Temus W; Warf 42; Warf Compound 42; Warf-12; Warfarat; Warfarin +; Warficide; Zoocoumarin When used as a rodenticide it is formulated as colorless baits containing 250-1000 mg active ingredient/kg. Source: IPCS INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY Health and Safety Guide No. 96 WARFARIN HEALTH AND SAFETY GUIDE www.inchem.org/documents/hsg/hsg/hsg096.htm

11. The Dose Differentiates the Poison • Probable lethal oral dose -- 50 to 500 mg/kg • Total of 1000 mg over 13 days fatal (adult man) ~ 1.1 mg/kg per day • IPCS INTERNATIONAL PROGRAMME ON CHEMICAL SAFETY Health and Safety Guide No. 96 WARFARIN HEALTH AND SAFETY GUIDE • Initial therapeutic dosage – 0.03-0.07 mg/kg-day • About 15X separates therapeutic and lethal doses

12. The “Good Chemicals” are Toxic too • Everything in List B is also associated with toxicity List B Oxygen Water Chromium (picolinate) Vitamin A Digoxin

13. Some medicinesstarted off aspoisons • Atropine – stimulant • neurological propertiesrecognized from poisonings • Purified from Deadly Nightshade • Digoxin, Digitalis – cardiac medications • Useful dosages of extract from Foxglove

14. 18th Century Doc Learns the Dose-Response Lesson The extract of Foxglove is highly poisonous. This extract was the poison used in Medieval Times for the ritual known as “Trial By Ordeal”! In 1775 Scottish doctor William Withering, who had written a book on botany, had a very sick patient. After telling him he was going to die, the patient went to a local gypsy, who gave him an herbal remedy. He immediately got better! Dr. Withering demanded that the gypsy show him the remedy and was surprised to discover it to be Foxglove, a plant he thought was poisonous! Dr. Withering brought Foxglove to the world of medicine…. This extract became known as Digitalis, one of the most important heart medicines of today! The Foxglove Story Source: www.webplastics.com/botoxcoll.htm

15. Critical Concept # 1 • No matter how “good” or “bad” the associationswith a given chemical: The relevant or potentialdose determines the risk of undesired outcomes

16. Biology Survives on Chemistry • Energy, Communication,Sensory Control – depend on processing complex chemicals • Biochemistry is blind –nothing unique about “toxic” chemicals • Illustrations: • Hormone mimics • Bioremediation • Bioactivation

17. Detoxification Driven by the Liver • Tremendous capacity,extensive detoxification biochemistry • Control byenzymes that respond to chemical’s presence • Foreign chemicals “deactivated” then packaged for excretion

18. Additional Detoxification Organs • Kidneys • Lungs • Skin Pop Quiz: What are the two largest tissues/organs?

19. Critical Concept # 2 • Biological organisms arechemical-utilizing machineswith highly evolved protectivefeatures The form, amount, and timing of chemical exposures (back to dose again) is critical to the balance between detoxification and toxicity

20. Dose-Response Characteristics • How changes in dose cause changes in response – toxicity • Need to know because this describesPotency : Little more = Lot worse vs. Lot more = Little worse • Graphical representation common

21. Classic Dose-Response Curve • Flat region then response increases with dose

22. Thresholds of Effect • Steepness corresponds to Potency • Inflection points –Threshold; Maximal Response

23. Difficult to Reach Toxicity Toxic, but not unusual Extra-ordinarily Toxic Potency Estimation Quiz Chemical – Botox Use – Injectable skin enhancement

24. Common Chemicals Can’t be THAT Toxic, Right? “Botox is one of the most popular cosmetic “mini-treatments” today. This procedure … requires no anesthesia or recovery. Overall, the vast majority of patients love this "quick fix" and return for a BOTOX boost as soon as the wrinkles begin to reappear!” Source: www.webplastics.com/botoxcoll.htm

25. Difficult to Reach Toxicity Toxic, but not unusual Potency Estimation Botox The most potent substance known Botulinum Toxin used as the example of extreme potency in most texts – 50,000,000 times more toxic than DDT

26. Human Health Toxicity Assessment • Need to predict safe exposurelevels – occupational,environmental • Aim for extrapolation to sensitive individuals • Type of Response • Carcinogen • Non-carcinogen/systemic toxic effects • Numerical toxicity values • Cancer Slope Factor (CSF) • Exposure limit / reference dose (RfD)

27. Non-Cancer Value Derivation – Using the Threshold • Start from:NO-OBSERVABLE-ADVERSE-EFFECTS-LEVEL (NOAEL) • This conservatively estimated to be below the threshold level • Adjust downward to account for uncertainties RfD or TLV or PEL = NOAEL / UF

28. Toxicity Value Adjustment -- Uncertainty Factors • 10 for species X • 10 for sensitive individuals X • 10 for Less-than-Chronic studies X • 10 for LOAEL to NOAEL X • 3-10 for Incomplete database • Generally total at least 30; 1,000 is common

29. Cancer Toxicity Values – Using a Straight Line • Cancer Slope Factor -- slope of the dose-response curve for cancer • Assumes the curve doesn’t flatten out -- there is no threshold. • Extend dose-response curve as a straight line all the way to zero • Certain chemicals are best represented by other models

30. Why Cancer’s Different • Early recognition of theoretical basis for cancer to be a non -threshold phenomenon • Developed from radiation effects on chromosomes and “one-hit hypothesis” • Risk not seen as function of detox “processing” capacity being overcome • Instead, chance physical interaction between chemical and DNA resulting in mutation

31. Theoretically – No Threshold • Assuming no detox., then no threshold exists • Dose-response can no longer be flat below threshold • Requires extrapolation of dose-response curve through low-dose region

32. Straight-Line Extrapolation • Requires extrapolation through low-dose region • Protective to extrapolate all the way to “0”

33. Comparison of Dose Response Assessments Slope Factor Carcinogens Response Non-Carcinogens Response Reference Dose Dose

34. From Simple to Sublime… • Physiology and biochemistry are NOT simple, mono-phasic processes • Defense/detoxification mechanisms must be overcome (saturated) • Alternate “handling” can be stimulated or present in certain individuals • Multiple responses occurring, interacting

35. Simplification, not Simplistic • Scientists not ignorant of dose-response complexities • Pharmacologists capitalize on multiphasic responses • Microbiologists understood stimulation at low doses • Simplifications of dose-response toxicity simply sufficient, for a time….

36. Cancer Thresholds Observed in Practice

37. Observations Displace Theory • Many chemicals require biotransformation and INTERMEDIATES are carcinogens – at low concentrations, the abundance of detox capacity drives reactions too quickly for intermediates to build up • DNA repair mechanisms must be overwhelmed • Epigenetic (non-mutation) basis for cancer now well established

38. Hormesis: New Curve Shapes • Primarily a function of scale or resolution – looking in the low-dose tail • Upside-down U’s and J’s • Demonstrate more than one peak, or shift in dose-response direction

39. Response Dose Higher Dose = Lower Effect ? 0.1 mg/kg 0.2 mg/kg 0.1 mg/kg 0.3 mg/kg Low doses stimulate a response, which is subsequently reduced

40. Watch the Dose Scale … Response 0.2 mg/kg 2 mg/kg 20 mg/kg Dose

41. Good Outcomes Below NOEL Source: Jayjock, M.A. & Lewis, P.G. (2002) Implications of Hormesis for Industrial Hygiene. BELLE Newsletter 10: 2

42. Hormesis: Rule or Exception • Long documented phenomenon, • Marginalized from application in risk assessment • Association with homeopathy • Lack of low dose testing

43. Hormesis Exists for: • Low-dose radiation • Stimulation of repair mechanisms • Benzene • Ethanol • PAHs (combustion products) • Drugs • Hormones (feedback loops)

44. Reasons for Shape-Shifting • Chemical modulates its own tox/detox processes • Feedback loops with other chemicals/signals •  Antagonistic OR Stimulatory • Recruitment of a secondary stimulus – “Call for help” • Feedback Inhibition -- the response may reach a level where it stimulates antagonistic mechanisms

45. Examples of Modulation • Stimulation -- Phenobarbital induces P450 3A family – responsible for multiple drug/chemical metabolic processing • Inhibition: • PAH mixtures less potent carcinogens than the carcinogenicity of the individual chemicals would dictate • Inhibition of P450 enzymes by some PAHs slows metabolism needed for carcinogen formation from others

46. Hormesis Concerns • Incorporating any “allowance” for positive effects at low doses reduces protection • What if there are additional unknown negative effects?

47. Response Dose We could be missing low-dose, highly toxic responses

48. Good “U’s” Aren’t Only Shape Source: Jayjock, M.A. & Lewis, P.G. (2002) Implications of Hormesis for Industrial Hygiene. BELLE Newsletter 10: 2

49. Beyond Hormesis – Other Complex Dose-Responses • Metabolism Dependent Effects • Stimulation or antagonism of detox processes • Some enzyme synthesis is upregulated by presence of substrate • Example: Cytochrome P450 Induction • Can increase or reduce toxicity by supplementing or removing toxic form

50. Drug Modulating Metabolism Disulfiram changes metabolic profile for ethanol: • Ethanol metabolism classically proceeds via acetaldehyde then acetate formation • Disulfiram -- Antabuse • induces (along with ethanol) cytochrome P450 2E family responsible for ethanol metabolism • blocks enzyme responsible for conversion to acetate • Result is acetaldehyde buildup -- Highly unpleasant