1. The Long Term Effects of Pesticide Exposure on Human Health An Update on Recent Studies Study Issues Skin Problems Respiratory Problems Reproduction Nervous System Cancers Helen Murphy, FNP-MHS Pacific Northwest Agricultural Safety and Health Center University of Washington

2. Problems Studying Long Term Effects Time delay between exposure and health outcome Attribution: is it from pesticides or something else? Attribution: is it from pesticides or something else? –Other factors Poor exposure assessment Poor exposure assessment – by location – by job classification – recall bias Incomplete information on health outcomes Incomplete information on health outcomes What goes unpublished? What goes unpublished?

3. Studying Long Term Effects Exposure 1.Location 2.Job Title 3.Equipment Sales 4.Use questionnaire 5.Biological monitoring Health Problem 1.Questionnaires 2.Medical Records 3.Cancer Registries 4.Clinical Measurements Intervening Factors Diet Genetics Illnesses Smoking Other Chemicals Environmental Factors Intervening Factors

4. How do we study the long term health effects of pesticides? Case series cases seen by a doctor cases seen by a doctor Ecological comparing two geographic regions Cross sectional snap shot survey Case-control compare exposures of people with and without a health problem Cohort follow exposed and unexposed people to see who gets the health problem Randomized controlled trial (RCT) experimental - animals

5. Random assignment Non-random assignment Analytic: comparison group OBSERVATIONAL: No control over who is exposed and non- exposed EXPERIMENTAL: Control over who is exposed and non- exposed * Clinical trials (e.g. symptoms from spray with toxic pesticide vs. spray with non-toxic pesticide) * Community intervention studies (e.g. community’s health after IPM vs. after pesticide use) Descriptive: no comparison group Observational vs. Experimental

6. Descriptive Studies - no comparison group- Case reviews: Investigate cases of pesticide poisoning (e.g. LNI investigated cholinesterase depressions) Surveillance: Report cases of poisoning (e.g. Pesticide Incidence Reporting and Tracking PIRT program) Survey: Pesticide use and health problems

7. Analytic: Comparison Group Case Control: Select cases with or without the health problem and look back to compare their exposures or non- exposure Cohort: Select exposed and non exposed (pregnant sprayers and pregnant non- sprayers) then follow over time to determine health outcome Cross Sectional: Compare present health problem and exposures at one point in time Retrospective Cohort: Select groups (cohorts) who are exposed and unexposed (sprayers vs non-sprayers) and look back at their health outcomes (pregnancies) ECOLOGICAL : Compare rates of a pesticide health problem in 2 populations by exposure areas Community Level Past Future RETROSPECTIVEPROSPECTIVE Now Individual Level

8. Information Sources Pesticide Literature Review 1990 – 2003 – 12, 061 papers: 30 reviews/254 primary – Rated by quality scoring 1-7 – Summary conclusions and evaluation Mother-Child Pair Studies Mother-Child Pair Studies – Exposures measured with bio-markers (urine, blood, personal air monitors) – Data on intervening factors (smoking etc) – Clinical measurements on children

9. Sources US Agriculture Health Study n=89,658 Sample: recruited from Sample: recruited from 1993 – 1997 – –Private applicators: 52,395 – –Spouses: 32,347 – –Commercial applicators: 4,916 Detailed questionnaires: (validated) – – Pesticides: kinds, frequency, application practices – – Lifestyle: diet, exercise, smoking, alcohol – – Medical history: personal and family – –Other farm exposures: solvents etc…. Cancer and non-cancer outcomes: – –Cancer registries – –Vital statistics – –Interviews

10. Skin Problems

11. Skin: Primary exposure route of pesticides Most common effect is contact dermatitis – Allergic – Irritant 15-25% pesticide illness reports 15-25% pesticide illness reports

12. Coexisting Factors in Agricultural Workplace Plant materials Plant materials Solvents Solvents Fuels Fuels Rubber Rubber Cleansers Cleansers Creams Moisture Cold temperatures Physical abrasions

13. Skin Problems Fungicide induced irritant or allergic dermatitis  Dithiocarbamates Maneb (MANEX, PENTATHLON) Mancozeb (DITHANE) Thiram (ROOTONE, PROSPER) Zineb (NR)  Sulfur  Benomyl (nr)  Captan ( BONIDE, ENHANCE )  Chlorothalonil ( APPLAUSE, BRAVO ) Source: M.A. O’Malley, Skin reactions to pesticides, Occup Med State Art Rev 12 ([1997]2): 327–45.

14. Skin ProblemsInsecticides  Miticide: propargite  OP’s: skin sensitizers Intermittent dermatitis reports in Wa and Ca Malathion and Chlorpyrifos  Carbamates: Reported cases in Wa with carbaryl  Pyrethroids – Topical (skin surface) irritation and paresthesias

15. Skin Problems Soil fumigants can cause irritant dermatitis and chemical burns – methyl bromide (TRI-CON) – metam sodium (VAPAM) Herbicides - induced irritant or allergic dermatitis – paraquat – diquat – highly irritating – 53% paraquat applicators had a rash or burn in one study* * Source: Castro-Gutierrez N, McConnell R, Andersson K, Pacheco-Anton F, Hogstedt,C. Respiratory symptoms, spirometry and chronic occupational paraquat exposure. Scand J Work Environ Health 1997;23:421–427.

16. Severe Contact Dermatitis Cartap + [Fenobucarb, Dimethoate and Methyl Parathion x 20 yrs]

17. Respiratory Problems A few pesticides are ‘sensitizers’ causing allergic reactions along with OTHER triggers –dusts, pollens, animals, diesel, molds, grains, hay, disinfectants Organophosphates and carbamates inhibit cholinesterase resulting in –Constriction of the bronchial tubes –Increased secretions –Difficulty in breathing

18. Respiratory Problems Insecticide related wheezing with*: –parathion (NR) –Chlorpyriphos (Lorsban/Dursban) –malathion ( MAXIDE) Herbicide related wheezing with*: –paraquat –Atrazine (Shotgun…95 labels) –Alachlor (Lasso) –chlorimuron ethyl (NR) –EPTC ( EPTAM, ERADICANE) *Source: Hoppin JA et al (2006). Pesticides and Adult Respiratory Outcomes in the Agricultural Health Study. Ann. New York Academy of Sciences. 1076:343-354.

19. Chronic Bronchitis in Farm Women and Pesticides Insecticides Dichlorvos (Fulex/ Vapona) Dichlorvos (Fulex/ Vapona) DDT DDTHerbicides Cyanazine (Bladex) ParaquatFumigant methyl bromide methyl bromide Source: Valcin M, et al. Chronic bronchitis among nonsmoking farm women in the agricultural health study. J Occup Environ Med. 2007 May;49(5):574-83. Controlling for: Smoking 2 nd hand smoke Asthma Usual suspects: dust, solvents, manure

20. Reproductive Menstrual Cycles Menstrual Cycles Birth defects Birth defects Time to pregnancy Time to pregnancy Small for Age at Birth Small for Age at Birth Miscarriages Miscarriages

21. Women using pesticides have 1.5 x increased odds of * Women using pesticides have 1.5 x increased odds of * Longer cycles Longer cycles Missing a period Missing a period Hormonally active pesticides increase odds of missed periods, long cycles, bleeding mid cycle. Hormonally active pesticides increase odds of missed periods, long cycles, bleeding mid cycle.LindaneAtrazine Mancozeb or Maneb Source: Farr SL, Cooper GS, Cai J, Savitz DA, Sandler DP. Pesticide use and menstrual cycle characteristics among premenopausal women in the Agricultural Health Study. (2004). American Journal of Epidemiology, 160(12):1194-204. Menstrual Cycle Changes

22. Birth Defects: Study Design Issues Indirect exposure measurements without biomarkers: Indirect exposure measurements without biomarkers: Work records Work records Places of residence Places of residence Databases Databases Questionnaires Questionnaires Only cases that survive birth are counted ( miscarried fetuses? )

23. Birth Defects Consistent findings with Limb reductions - Uro-genital defects Central nervous system Cleft palates/lips: marginal significant w/maternal exposure Eye – heart defects Not definitive until better exposure analysis with the US Children’s Health Study Source: Sanborn M, Cole D, Kerr K, Vakil C, Sanin LH, Bassil K. Pesticides Literature Review. Ontario College of Family Physicians. Toronto 2004.

24. Time to Pregnancy S tudies suggest that occupational exposure increase time needed to become pregnant S tudies suggest that occupational exposure increase time needed to become pregnant 20%  in women engaged in pesticide activities + husband also engaged in same– but imprecise due to small numbers Associated with dicamba, glyphosate, 2,4-D, thiocarbamates, OP’s although not statistically significant Source: Curtis KM, Savitz DA, Weinberg CR, Arbuckle TE. The effect of pesticide exposure on time to pregnancy. Epidemiology. 1999 Mar;10(2):112-7.

25. Probable link Probable link Fetal and maternal blood samples for OP by-products and newborn lengths Fetal and maternal blood samples for OP by-products and newborn lengths Chlorpyrifos and diazinon [by- products measured in fetal and maternal blood] associated to lower birth weight and length* Chlorpyrifos and diazinon [by- products measured in fetal and maternal blood] associated to lower birth weight and length* Small for Age at Birth * Whyatt RM et al. Biomarkers in assessing residential insecticide exposures during pregnancy and effects on fetal growth.Tox Applied Pharm 206 (2): 246-254 AUG 7 2005

26. Miscarriages S tudies suggest an association Critical exposure windows and certain pesticides One - four months before conception One - four months before conception Non use of PPE increased risk 5 fold in one study Non use of PPE increased risk 5 fold in one study Study Method Problems No data on miscarriage rates in general population High % go undetected ?? Role of other farm toxins (animal viruses, heavy metals) largely unknown in studies Sources: Arbuckle et al 1999 and 2001; Garry VF et al 2002

27. Health Risks to Children AsthmaCancers Neuro-developmental problems Small for age at birth Congenital defects

28. Asthma Children exposed to herbicides in 1 st year of life 4.5x greater risk of developing asthma before age 5. insecticides 2.4x Source: Salam MT, Li YF, Langholz B, Gilliland FD. Early-life environmental risk factors for asthma: findings from the Children's Health Study. Environ Health Perspect. May 2004;112(6):760-765.

29. The Agriculture Health Study Cancers in Children All cancer incidence: a third higher than rates in general population All cancer incidence: a third higher than rates in general population All lymphomas 2 x higher - Hodgkin's 2.5 x higher All lymphomas 2 x higher - Hodgkin's 2.5 x higher Exposure risks Exposure risks   risk if father NOT use chemically resistant gloves  NOT associated to parental application frequency   risk with aldrin (2.66) but not a known carcinogen Limitations: only 5 year follow up and small numbers Limitations: only 5 year follow up and small numbers Source: Flower KB, Hoppin JA, Lynch CF, Blair A, Knott C, Shore DL, Sandler DP. Cancer risk and parental pesticide application in children of Agricultural Health Study participants. Environ Health Perspect. 2004 Apr;112(5):631-5.

30. Nervous System Mental Health Mental Health Neurological Symptoms Neurological Symptoms Parkinson’s Disease Parkinson’s Disease

31. Mental Health Depression, emotional disorders and suicides* –Earlier poisonings ~ minor depression –Canada suicides ~ pesticide use US Agriculture Health Study – wives of pesticide applicators US Agriculture Health Study – wives of pesticide applicators –Self report or MD diagnosed depression in women 3.26 x higher risk if earlier poisoning** ** Beseler C, et al. Depression and Pesticide Exposures in Female Spouses of Licensed Pesticide Applicators in the Agricultural Health Study Cohort. J Occ Env Med Volume 48, Number 10, October 2006. * Sanborn M, Cole D, Kerr K, Vakil C, Sanin LH, Bassil K. Pesticides Literature Review. Ontario College of Family Physicians. Toronto 2004.

32. Adult Nervous System Problems Subtle diminished function of nervous system – Occur after severe acute poisonings (OPIDN) – Chronic low level exposure Self-reported neurologic symptoms associated with cumulative exposure to moderate levels of fumigants, organophosphates, organochlorines* Self-reported neurologic symptoms associated with cumulative exposure to moderate levels of fumigants, organophosphates, organochlorines* * Kamel F, et al Neurologic Symptoms in Licensed Private Pesticide Applicators in the Agricultural Health Study. Environ Health Perspect 113:877–882 (2005).

33. Parkinson’s and Pesticides New cases among applicators associated to overall use, cumulative days (years x frequency) of pesticide application (2.3 risk), hazardous practices, and some specific pesticides. –High exposure event (spill) and not bathing w/in 1 hour –Use of PPE was protective Evidence shows an association but questions remain – Is it a causal relationship? – Is it related to any particular pesticide? – Is it a combination of a pesticide and another toxicant? Kamel F. et al. Pesticide Exposure and Self-reported Parkinson’s Disease in the Agricultural Health Study. Am J Epidemiol 2007;165:364–374

34. Cancers Brain Tumors Brain Tumors Breast Breast Pancreatic Pancreatic Lymphomas Lymphomas Leukemia Leukemia Kidney Prostate Lung Ovarian

35. Brain Tumors 5 Cohort Studies (all retrospective cohorts) all + Exposure estimations problematic Exposure estimations problematic Association membership Association membership Pesticide licensees: use or not Pesticide licensees: use or not Pesticide and application equipment purchases* Pesticide and application equipment purchases* Residence in high pesticide using areas Residence in high pesticide using areas Norwegian Study*: one type of tumor (non- astrocytic neuroepithelial) >3 x risk Norwegian Study*: one type of tumor (non- astrocytic neuroepithelial) >3 x risk Kristensen P et al. Cancer in offspring of parents engaged in agricultural activities in Norway: incidence and risk factors in the farm environment. International Journal of Cancer. 1996; 65: 39–50.

36. Breast Cancer Previous studies: mixed results – some studies positive and some negative Previous studies: mixed results – some studies positive and some negative –Case/control ; 1.8 x risk if in field during spraying, 2.0 x if not use PPE US Agriculture Health Study unclear risk* : US Agriculture Health Study unclear risk* : –Proximity of farm to areas of pesticide application –Husband’s use of 2,4,5-TP and possibly dieldrin, captan, and 2,4,5-T New DDT study - 5 fold risk with exposure to DDT * New DDT study - 5 fold risk with exposure to DDT * – –p,p´-DDT measured exposure at < age 20 **Cohen et al. (2007) DDT and Breast Cancer in Young Women: New Data on the Significance of Age at Exposure. EHP. 115(10) 1406-1414. *Engel L, et al (2005). Pesticide Use and Breast Cancer Risk among Farmers' Wives in the Agricultural Health Study American Journal of Epidemiology, 161: 121-135.

37. Other Cancers Pancreatic: Aerial applicators (9,961) 2.71x risk than flight instructors (9,969) Non Hodgkin’s Lymphoma [ Immunologic + environmental factors] : 23/27 studies positive. 2-4 D a precipitant. Leukemia: 14/16 studies positive Kidney : Increased mortality rates on pentachlorophenol chemical company workers Source: Sanborn M, Cole D, Kerr K, Vakil C, Sanin LH, Bassil K. Pesticides Literature Review. Ontario College of Family Physicians. Toronto 2004.

38. US Agriculture Health Study Cancer Outcomes Prostate: 5,322 male applicators 3.75 risk > age 50 with methyl bromide or chlorinated pesticides ( organochlorines like DDT or endosulfan) Lung: (non smokers) Dose-response with 2 herbicides and 2 insecticides –metolachlor (OR) = 5.0 in highest exposure group –pendimethalin (OR) = 4.4 –chlorpyrifos (OR) = 1.9 –diazinon (OR) = 3.7 Ovarian: Female applicators 3 x more cases than general population

39. THE END &

40. Research Websites The US Agricultural Health Study The US Agricultural Health Study http://aghealth.nci.nih.gov/ Columbia Center for Children’s Environmental Health Columbia Center for Children’s Environmental Health http://www.mailman.hs.columbia.edu/ccceh/pesticides.html CHAMACOS Center for the Health Assessment of Mothers and Children of Salinas CHAMACOS Center for the Health Assessment of Mothers and Children of Salinas http://ehs.sph.berkeley.edu/chamacos/ The National Children’s Study The National Children’s Study http://www.nationalchildrensstudy.gov/

41. Pesticide Information Websites PICOL-Pesticide Information Center On Line WSU http://picol.cahe.wsu.edu/LabelTolerance. html http://picol.cahe.wsu.edu/LabelTolerance. html PAN Pesticides Database: http://www.pesticideinfo.org/index.htm PAN Pesticides Database: http://www.pesticideinfo.org/index.htm http://www.pesticideinfo.org/index.htm CDMS Agro Chemical Database CDMS Agro Chemical Database http://www.cdms.net/LabelsMsds/LMDef ault.aspx

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