1. Fred Berman Oregon Institute of Occupational Health Sciences Oregon Health & Science University

2. Chronic sequelae following acute poisoning Knowledge based on clinical experience Primarily neurological Effects from chronic low-level exposure Knowledge based on epidemiological & animal studies Neurological/neurodevelopmental Cancer Endocrine effects (endocrine disruptors) Asthma

3. Residual neurological impairment secondary to multi-organ failure or hypoxia neuropsychiatric sequelae (OPs) Subtle effects Revealed by neuro-behavioral testing Delayed Peripheral Neuropathy (OPIDN) some OPs damage afferent fibers of periph & central n s inhibit neuropathy target esterase (NTE)-PNPLA6 weakness or paralysis & paresthesias of the extremeties Intermediate syndrome 1-4 days post-exposure acute respiratory paresis and muscular weakness lasts days to weeks

4. Less well understood consistent evidence of neurodevelopmental effects from chr. low- level gestational/neonatal exposure chr. arsenic exposure effects well documented assoc. w/ other purported effects often tenuous Based on epidemiological or animal studies diseases with low incidence difficult to evaluate statistical association ≠ causation often good for hypothesis generation most common shortcoming is adequacy and reliability of the exposure assessment Conditions supportive of a potential cause/effect relationship temporal relationship, strength of effect, dose-response, consistency, bio. plausibility, experimental support, analogy

7. Children vs adults differences in physiology and behavior spend a lot of time on the floor frequent hand-to-mouth activity food, water, substance intake are proportionally larger per unit body weight higher metabolic rate dietary composition is different (e.g. higher intake of apple products)

8. Neurodevelopmental effects most studies focus on OPs and OCs far fewer studies on others, including pyrethroids, as well as on herbicides and fungicides Preschool Children adverse behavioral effects of prenatal OPs at birth in both agricultural and urban settings pre- and post-natal hexachlorobenzene assoc w  ADHD scores prenatal DDT assoc w  psychomotor development at 6 & 12 months, but not at 24 months age prenatal chlorpyrifos  both motor and mental fx @ 3 yrs

9. School-Age Children Organochlorines consistent assoc of ADHD and ASD with maternal proximity to applications during the period of CNS embryogenesis ADHD consistent assoc with PCBs and DDE Organophosphates assoc between ADHD and urinary metabolites, as well as w prenatal exposures Poor nutrition may increases the adverse effects on neurodevelopment

10. Adults two types of studies: x-sectional and long. studies of occupationally exposed wide range of outcomes similar populations and specific dz outcomes, e.g. Parkinson’s dz x-sect study of PCOs and OPs decr. vibration sense and nm function temporal assoc. noted farmworkers (proxy for pest. exp.) decr. performance on several neurobehav. tests strong temporal association PCOs assoc w symptoms of headache, depression, fatigue, etc. strongest assoc. w fumigants, OPs and OCs physician-dx depression assoc. w acute poisoning, hi exposure event and hi cumulative exposures

11. Adults Parkinson’s Disease several studies temporal association pos assoc w dieldrin tissue levels biological plausibility warrants further mechanistic studies animal studies support mechanistic association dose dependent assoc w fungicides (mancozeb and maneb) manganese ion and organic component both contribute to the toxicity other pesticides include 2,4-D, paraquat, diquat, permethrin, dieldrin and rotenone

12. Children Most compelling associations are leukemia and brain tumors rarity of the disease forces lumping of tumor types Leukemia most common exposure related to household insecticide use during pregnancy and preconception periods mixing tumor types and recall bias limited these studies higher-quality studies have found statistically sig associations

13. Children Childhood brain tumors also assoc w household use of pesticides prenatal insecticide exposure as well as maternal/paternal occup exp pre-conception through birth represent the most consistent risk factors Overall, relatively consistent evidence for increased risk of childhood cancers following preconeption and/or prenatal exposure to pesticides. Maternal exp to insecticides and paternal occup exp carry the greatest risk

14. Adults Non-Hodgkin lymphoma and other blood cancers lack of sufficient exposure information is a limitation class, rather than specific pesticides listed (herbicides and insecticides) one well-designed study listed risks for mecoprop (chlorophenoxy herbicide) another study listed MCPA and glyphosate as risk factors incr. risk for NHL associated w 2,4-D also listed

15. Adults Prostate caner may be related to hormonally active pesticides carbofuran, permethrin aldrin and DDT higher risk estimates found for methyl bromide other meta studies found no association w prostate cancer further studies found assoc. w OCs, incl. DDT, dicofol and tetradifon Kidney cancer – four studies w positive associations Other associations Pentachlorophenol and soft tissue sarcoma, renal and GI cancer Arsenic and lung, bladder & skin cancer

16. Precocious puberty – DDE – not conclusive Altered lactation – DDE Breast cancer – unclear associations Female fertility – limited evidence – no sp. pesticide Semen quality dioxins & PCBs, but not strong w OCs sig. evidence for assoc w some non-persistent pesticides Male urogenital malformations – limited evidence Reproductive neuroendocrine systems – limited data in humans, stronger animal data Thyroid function – female spouses of farmworkers OCs, inc. aldrin, DDT, heptachlor, lindane and chlordane benomyl and paraquat – hypothyriodism mancozeb and maneb – hypo- and hyperthyroidism

17. Pyrethrins OPs chlorpyrifos, diazinon, parathion incr. airway reactivity