Fred Berman, DVM, PhD Director, Toxicology Information Center

1. Factors that Increase Risk from Pesticide ExposureorMore reasons to use caution when handling pesticides Fred Berman, DVM, PhD Director, Toxicology Information Center Oregon Institute of Occupational Health Sciences Oregon Health and Science University

2. The Essence of Toxicology • “All substances are poisons; there is none which is not a poison. The right dose differentiates a poison and a remedy.” Theopharastus Phillipus Aureolus Bombastus von Hohenheim (Paracelsus, 1493-1541)

3. Dose-Response Curve NOAEL Examples: Edrophonium, pyridostigmine, Metrifonate - acetylcholinesterase inhibitor drugs, have same mechanism of action as organophosphate and carbamate insecticides Is this “toxicity rating” ≈ EPA mileage rating?

4. Toxicity Examples: Deltamethrin LD50 (rat) 30 mg/kg in oily vehicle, >5000 mg/kg in aqueous vehicle Malathion LD50 (rat) 1000-10000 mg/kg Chlorpyrifos LD50 (rat) 95-270 mg/kg

5. Where is Your NOAEL? The Laboratory World vs The Real World • Rat: • Genetically homogenous • Narrow age range • Narrow weight range • Highly standardized nutrition • 12 hr light/dark cycles • Temperature and humidity control • Controlled physical activity • Controlled-stress environment • Human: • Genetically heterogenous • Wide age range • ‘Wide’ weight range • Nutrition all over the map • Variable sleep/wake cycles • Temperature/humidity variable • Physical activity highly variable • Stress is a part of life

6. Factors that increase susceptibility to adverse effects from pesticide exposure will…… • Increase absorption • Alter distribution • Reduce metabolism • Reduce Excretion • Alter toxicological response

7. Age as a Risk Factor Aging is as much biological as chronological

8. Effects of aging on pesticide absorption • Thinning of skin • Facilitates more rapid absorption • More easily damaged upon pesticide contact • Slower to show signs of irritation • Nervous system changes • − Alterations in smell, taste and touch sensations • reduce ability to detect and avoid More rapid absorption combined with increased time of contact add up to a larger dose

9. Effects of aging on pesticide distribution • Loss of muscle mass and increased body fat • Many pesticides stored in body fat prior to removal by liver and kidneys • Fat-soluble pesticides can build up to higher levels • Distribution of pesticides in blood and other body fluids • Aging liver and kidneys are slower to remove • Reduced plasma proteins Older adults may experience health problems from pesticide exposures that would not cause problems for younger adults

10. Effects of aging on pesticide metabolism and excretion • Reduced cardiac function • Reduces blood flow to liver and kidneys • Reduced size of liver and kidneys • reduces metabolism and excretion • Proportionally more susceptible to injury • Reduced plasma esterases Reduced cardiac, liver and kidney function work together to reduce the metabolism and excretion of pesticides The half-life of drugs processed by the liver or excreted by the kidneys is 50-70% longer in those older than 65 years.

11. Other factors that alter susceptibility to pesticide toxicity in the aged • Increased use of pharmaceuticals • May alter pesticide absorption, metabolism, distribution and excretion • e.g. heart meds, diuretics, skin cremes, steroids • Drug/pesticide interactions • e.g.: pyridostigmine and OPs/carbamates • Polypharmacy • Diseases of aging • Can further alter pesticide absorption, distribution, metabolism and excretion • Diabetes, hypertension, liver and biliary cirrhosis, etc.

12. Heat and HumidityWork and Exercise

13. Heat and HumidityWork and Exercise

14. Heat and humidity • Effects on absorption • Disinclination to wear PPE • Increased skin permeability as temp. increases • Activation of sweat glands • Dermal hydration increases • Vasodilatation • Increased heart rate • Increased respiration (rate, depth) • Increases intake of airborne pollutants • Transfer from sweat to hands to mouth, etc.

15. Heat and humidity • Transdermal absorption of parathion in human volunteers (Funckes et. al., 1963) • Increased 17% when temperature raised from 21° to 28° C (70-82 F) • Increased by 227% when temperature raised from 21° to 40.5° C (70-105 F) Factoid: Parathion and other anticholinesterase insecticides directly stimulate sweating, hence dosage can be exacerbated in a warm, humid environment due to increased sweating combined with greater transcutaneous absorption across moist skin.

16. Heat and humidity Plasma cholinesterase levels in lawn care workers in Florida, 1987 (Yeary et. al., 1993)

17. Heat and humidity • Effects on intrinsic toxicity: there is a positive correlation between core temperature and sensitivity to chemical toxicants. • Mouse LD50 (i.p.) parathion, carbaryl, DDT • @ 1 C (34 F): 16.5, 263, 750 mg/kg • @ 27 C (81 F): 29, 588, 1175 mg/kg • @ 38 C (100 F): 11.3, 112, 875 mg/kg Temperature affects toxicity through impaired heat regulation, water loss, respiratory / circulatory disturbances, basal metabolism changes, and altered individual reactions.

18. Heat and humidity Impact of the average air temperature on daily mortality in humans (Kunst et. al., 1993)

19. Other Factors that Increase Absorption • Sunscreens, insect repellents, alcohol consumption • Increase dermal absorption of 2,4-D and other pesticides • DEET increases dermal absorption of permethrin • DMSO • Used as anti-inflammatory (e.g. arthritis) in horses • A big no-no if handling pesticides! • “Inert” ingredients • Emulsifiable concentrates….dermal hazard • Some can be caustic to human skin • Some areas of the body, absorption rates are higher • Genital area ~ 12x more absorptive than forearm

20. Other factors that may increase exposure • Worker risk perception • Perception of control • Lack of control, less likely to use safe practices • Being informed increases perception of control • Personal hygiene (fastidious behavior) • Hand washing • Work clothes transport, storage and laundering • Likelihood to delay decontamination • Smoking, drug use

21. More other factors • Lack of sleep (disruption of circadian cycles) • Shift work • Reduced alertness – more apt to make mistakes • Increased physiological stress • Altered hormone levels • Pharmaceuticals • May compete for metabolic enzymes • Can inhibit metabolism • May compete for transporters and reduce excretion • Many pesticides interact with efflux transporters • Chlorpyrifos, malathion, acetochlor/dimetachlor • May alter protein binding • May alter physiologic processes

22. What have we learned? • An individual’s NOAEL can be reduced by factors that: • Increase absorption • Alter distribution • Reduce metabolism • Reduce excretion • Alter toxic responses • Age and Heat/Humidity are two major (but • not the only) factors that increase risk from • pesticide exposure

23. What Can We Do? • Always use best practices when handling pesticides. • Be aware of your individual intrinsic factors that may increase susceptibility to the adverse effects from pesticide exposure. • Recognize extrinsic factors that may increase susceptibility on any given day.