The Long Term Effects of Pesticide Exposure on Human Health An Update on Recent Studies • Study Issues • Acute Effects • Skin Problems • Respiratory Problems • Reproduction • Risks to Children • Nervous System • Cancers Helen Murphy, FNP-MHS Pacific Northwest Agricultural Safety and Health Center University of Washington
Problems Studying Long Term Effects • Time delay between exposure and health outcome • Attribution: is it from pesticides or something else? • Other factors • Poor exposure assessment • by location • by job classification • recall bias • Incomplete information on health outcomes • What goes unpublished?
Studying Long Term Effects Intervening Factors Exposure Health Problem • Location • Job Title • Equipment Sales • Use questionnaire • Biological monitoring Diet Genetics Illnesses Smoking Other Chemicals Environmental Factors • Questionnaires • Medical Records • Cancer Registries • Clinical Measurements Intervening Factors
How do we study the long term health effects of pesticides? • Case series 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
Observational vs. Experimental EXPERIMENTAL:Control over who is exposed and non-exposed OBSERVATIONAL: No control over who is exposed and non-exposed Random assignment Non-random assignment Descriptive:no comparison group Analytic:comparison group * 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 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
Analytic: Comparison Group Community Level ECOLOGICAL:Compare rates of a pesticide health problem in 2 populations by exposure areas Now RETROSPECTIVE PROSPECTIVE INDIVIDUAL LEVEL Past Future 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 Case Control:Select cases with or without the health problem and look back to compare their exposures or non-exposure Retrospective Cohort:Select groups (cohorts) who areexposedand unexposed (sprayers vs. non-sprayers) and look backat their health outcomes (pregnancies)
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 • Exposures measured with bio-markers (urine, blood, personal air monitors) • Data on intervening factors (smoking etc) • Clinical measurements on children
Sources US Agriculture Health Study n=89,658 • 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
Acute Effects • What is cholinesterase? • Effects of OP’s and Carbamates • Organochlorines • Pyrethroids • Paraquat
nerve cell After electrical nerve impulse transmission is completed, the body produces cholinesterase. Cholinesterase breaks up acetylcholine into acetate and choline. Electrical nerve impulse coming from nerve cell stimulates the body to produce acetylcholine. Acetylcholine acts as a bridge transmitting the electrical charge to the muscle cell. Muscles and glands contract. acetate choline muscle cell Normal Electrical Nerve Impulse Transmission Once acetylcholine is broken, it can no longer transmit electrical nerve impulses. Electrical nerve impulses stop and the muscles and glands are quiet
nerve cell Electrical nerve impulse acetate choline cholinesterase organophosphate atropine muscle cell If an organophosphate (Op) or carbamate is present, they bind with cholinesterase. [This is an irreversible effect with an Op but not with a carbamate] The bound cholinesterase cannot penetrate acetylcholine to break it up. The body continues to produce acetylcholine unimpeded. This results in a build up of acetylcholine with continuous electrical nerve impulse transmission and over stimulation of muscle and glands. Atropine relieves the over stimulation of the muscles and glands by reducing the amounts of acetylcholine. The effect only lasts 15 minutes. Therefore the dose must be repeated until the organophosphate binding effect has worn off. Organophosphate-Carbamate Disruption of Electrical Nerve Impulse Transmission Therapeutic Effect of Atropine
Signs and Symptoms of Acute Organophosphate [OP] Poisoning e.g. Phorate (Thimet) temephos (Abate), methamidiphos (Monitor)
Signs and Symptoms of AcuteCarbamate Poisoning e.g. carbofuran (Furadan) , methomyl (Lannate), thiodicarb (Larvin)
Signs and Symptoms of Acute Organochlorine [OC] Poisoning • Muscle Weakness • Dizziness • Headache • Numbness • Nausea • Loss of consciousness • Convulsions • Vomiting • Hand tremors • Staggering gait • Anxiety/restlessness • Confusion Central Nervous System e.g. endosulfan (Thiodan) and DDT
Signs and Symptoms of Pyrethroid Poisoning e.g. cypermethrin (Raid) , fenvalerlate (Everside) , deltamethrin (Suspend)
Paraquat Poisoning e.g. “Gramoxone, Parazone, Firestorm ”
Skin Problems • Skin: Primary exposure route of pesticides • Most common effect is contact dermatitis • Allergic • Irritant • 15-25% pesticide illness reports
Plant materials Solvents Fuels Rubber Cleansers Creams Moisture Cold temperatures Physical abrasions Coexisting Factors in Agricultural Workplace
Skin Problems • Fungicide induced irritant or allergic dermatitis - Dithiocarbamates • Maneb (MANEX, PENTATHLON) • Mancozeb (DITHANE) • Thiram (ROOTONE, PROSPER) • Zineb (NR) - Sulfer - Benomyl (nr) - Captan (BONIDE, ENHANCE ) - Chlorothalonil (APPLAUSE , BRAVO ) Source: M.A. O’Malley, Skin reactions to pesticides, Occup Med State Art Rev 12 (2): 327–45.
Skin Problems • Insecticides • 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
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.
Severe Contact DermatitisCartap + [Fenobucarb, Dimethoate and Methyl Parathion x 20 yrs]
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
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.
Chronic Bronchitis in Farm Women and Pesticides Insecticides • Dichlorvos (Fulex/ Vapona) • DDT Herbicides • Cyanazine (Bladex) • Paraquat Fumigant • Methyl bromide • Controlling for: • Smoking • 2nd hand smoke • Asthma • Usual suspects: dust, solvents, manure 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.
Reproductive • Menstrual Cycles • Birth defects • Time to pregnancy • Small for Age at Birth • Miscarriages
Menstrual Cycle Changes • Women using pesticides have 1.5 x increased odds of * • Longer cycles • Missing a period • Hormonally active pesticides increase odds of missed periods, long cycles, bleeding mid cycle. • Lindane • Atrazine • 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.
Birth Defects:Study Design Issues • Indirect exposure measurements without biomarkers: • Work records • Places of residence • Databases • Questionnaires • Only cases that survive birth are counted (miscarried fetuses? )
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.
Time to Pregnancy • Studies 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.
Small for Age at Birth • Probable link • 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* * 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
Miscarriages • Studies suggest an association • Critical exposure windows and certain pesticides • One - four months before conception • 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
Risks to Children More Vulnerable To Pesticides • Greater Exposure • Hand to mouth behaviors • SKIN contact with floors and lawns • Lighter less clothing • Eat and drink more per weight • Greater Absorption • Breathing rates • Heart rates • Skin surface/weight • Greater Sensitivity • Sensitive developing organs • Less ability to detoxify
Behaviors • Hand to mouth: Taste their environment • Near the ground: Spend more time on the ground • Outdoors: Spend more time outside • Diet: consume more per weight (water and fruits)
Diet • Drinks 2 x more water per their weight than an adult • Eats 12x more apples per their weight than an adult
Pesticides in Urine of 22 ChildrenBefore, During, and After Organic Diet Intervention Organic diet Conventional diet Conventional diet Lu C, Toepel K, Irish R, Fenske RA, Barr DB, Bravo R. Organic diets significantly lower children's dietary exposure to organophosphorus pesticides. Environ Health Perspect. 2006 Feb;114(2):260-3.
Biology- Higher Dose By: Skin More permeable: highest at birth 2.7 x more skin surface/weight than adults Lungs Inhales more per day (1.7x) than adult
Vulnerability to Health Effects: Organs Still Developing “A little kid goes from a single cell to a laughing, sociable, intelligent, friendly human being over the course of two years. That’s dramatic growth and development!” ~Kenneth Olden, PhD, former Director, National Institute of Environmental Health Sciences
Health Risks to Children • Asthma • Cancers • Neuro-developmental problems • Small for age at birth • Congenital defects
Asthma • Children exposed to herbicides in 1st 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.
The Agriculture Health Study Cancers in Children • All cancer incidence: a third higher than rates in general population • All lymphomas 2 x higher - Hodgkin's 2.5 x higher • Exposure risks • Risk if father does 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 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.
New Focus on OP’s Growing evidence shows that children and their developing nervous systems are at risk of neurodevelopmental effects with chronic, low level exposure (non-acute).
OP and Children:New York Cohort Study Following 700 mother/baby pairs for 7 years. • mother’s air intake for pesticides • mother’s blood • umbilical cord blood of baby