The Human Health Effects of Pesticide Exposure Acute Effects Skin Problems Respiratory Problems Reproduction Risks to Children Nervous System Cancers

Agriculture in Asia A Typical North Vietnamese Farming Village

Focus on OP’s Most commonly used insecticide in agriculture Children at risk for neurodevelopmental problems Most commonly used insecticide in agriculture Common cause of poisoning

Normal Electrical Nerve Impulse Transmission nerve cell 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. After electrical nerve impulse transmission is completed, the body produces cholinesterase. Cholinesterase breaks up acetylcholine into acetate and choline. acetate choline Once acetylcholine is broken, it can no longer transmit electrical nerve impulses. Electrical nerve impulses stop and the muscles and glands are quiet muscle cell

Organophosphate-Carbamate Disruption of Electrical Nerve Impulse Transmission Therapeutic Effect of Atropine nerve 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. muscle cell Electrical nerve impulse acetate choline cholinesterase organophosphate atropine

Signs and Symptoms in Adults Miosis Blurring Eye CNS Lungs GI Glands Muscle Heart Fatigue Dizziness Headache Tremors Ataxia Seizures LOC Coma Insomnia Mental Δ Tightness Wheezing Cough Rhinorrhea Weakness Cramps Fasciculations Abd. cramps Nausea Vomiting Diarrhea Drooling Sweating Tearing Tachy Brady  BP ↓ BP Exercise: Body Mapping

Parathion Story On the day her house was sprayed, previously healthy girl 4 months of age became irritable and seemed congested in her upper airway, with a thick whitish nasal discharge. Over the next several days these symptoms persisted, and she began to refuse food, developed a fever, more frequent bowel movements, and decreased sleep. On day 6, she was brought to the emergency department (ED) and was given iv antibiotics, fluids, oxygen, and a series of tests to determine infection status. She was discharged with a diagnosis of upper respiratory infection and a prescription for an antibiotic. That night the child got worse paramedics were called and she was transported by air ambulance to a pediatric intensive care unit . She was sleepy, dehydrated, and had black, foul-smelling stools showing blood coming from the upper intestines. The diagnosis was dehydration and high salt in her blood (sodium). She remained in the hospital for more than 1 week, receiving fluids and antibiotics. She was discharged home without medications, but she continued to have abnormal head movement. Fourteen months later her home was evaluated for methyl parathion contamination, and her urinary metabolite of methyl parathion was 89 . The general population reference range is 0-63.

Signs of Pesticide Poisoning in a CHILD Seizures Lethargic sleepy Coma Can be confused with the flu

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

Typical Pesticide Application North Vietnam

Respiratory Problems Insecticide related wheezing with*: parathion chlorpyriphos malathion Herbicide related wheezing with*: paraquat atrazine alachlor chlorimuron ethyl (Classic) EPTC Children exposed to pesticides in 1st year of life 4.5x greater risk of developing asthma before age 5. *Source: Agriculture Health Study: http://www.aghealth.org/

Transplanting Rice West Sumatra, Indonesia

Skin Disorders Dermatitis with any pesticide Allergic Contact 12%-68% prevalence of skin problems in agriculture Paraquat irritant/burn = 53% applicators in one study* Chloracne from dioxins: 2,4,5 –T (Agent Orange) and possibly 2,4 –D, diuron, linuron (Viktor Yushchenko * 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.

Paraquat Application by Burmese Migrant Workers in Thailand Mae Sot, Thailand

Skin Disorders Soil fumigants can cause irritant dermatitis and chemical burns methyl bromide dichloropropene (Telone) Metam sodium Herbicide induced contact or allergic dermatitis miticide propargite paraquat and diquat Fungicide induced contact or allergic dermatitis Maneb Mancozed Zineb Sulfur Ziram Benomyl Captan Source: Solomon G, Ogunseitan OA, Kirsch A. Pesticides and Human Health: A Resource for Health Care Professionals. PSR. 2000.

Methamidiphos Contact Dermatitis North Vietnam

Severe Contact Dermatitis Cartap + [Fenobucarb, Dimethoate and Methyl Parathion x 20 yrs] Prey Vang, Cambodia

Pesticides Associated to Allergic Contact Dermatitis* Acephate Benomyl Captan Carbaryl Chlorothalonil Chlorpyrifos DCNA Diazinon Dienochlor Dimethoate Ethoxyquin Fenbutatin-oxide Fluvalinate Folpet Malathion Mancozeb Maneb Norflurazon Omethoate PCNB Permethrin Pyrethrum Sulfur Thiram Vinclozolin Zineb Ziram *Source: M.A. O’Malley, Skin reactions to pesticides, Occup Med State Art Rev 12 ([1997]2): 327–45.

Mixing Pesticides Siem Riep Province, Cambodia

Reproductive Effects Birth defects: Difficult to study but consist findings w/ Limb reductions - Uro-genital defects Central nervous system Cleft palates/lips Eye – heart defects Glyphosate: 3.6 risk of neurobehavioral problems in offspring Time to Pregnancy: occupational exposure increase time needed to get pregnant 20%  in women engaged in pesticide activities Dicamba, glyphosate, 2,4-D, thiocarbamates, OP’s. Reproductive n=62 Congenital defects +: add to the growing body of evidence but still problems in designs.  risk limb, urogenital, CNS, orofacial, heart, eye. Glyphosate and pyridil derivatives Time to PG + : n=8 consistent ~ suggest occupational exposure causes  time to pregnancy Fertility ?: inconclusive-design problems LBW, prematurity, IUGR:? n=10 7/10 + pyrethroid and chlorpyrifos. One paper mixed and 2 negative. May be an association more study needed Fetal death + 9/11 positive assoc c/ SB or NND only 1 neg. Strong assoc w/ SaB or B defect and conventional pesticide prenatally vs IPM…phenoxy herbicides and SAB and hexachlorobenzene contaminated seeds in childhood and SaB

Growth Monitoring Clinic Lombok, Indonesia

Reproductive Effects Small for Age Births: 7/10 studies + Fetal and maternal blood samples for Op by products and newborn lengths Chlorpyrifos and diazon residentially ~ lower birth weight and length* Fetal deaths (still births, neonatal death, or miscarriages) 9/11 studies + Strong association to miscarriages farming households using conventional pesticides 3 months before conception compared to IPM farms * Source: 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

New York Study Following 700 mother/baby pairs for 7 years. mother’s air intake for pesticides mother’s blood umbilical cord blood of baby

New York City Study Fetal exposure to chlorpyrifos is associated with lower birth-weight and birth length Same effect as SMOKING- as if the mother was a heavy smoker At age 3 those more exposed had delayed movement and mental skills and attention deficits – temporary?

California Studies 600 pregnant Latina women farm working families living in Salinas, a heavy agriculture area. OP by-products in urine during pregnancy and after delivery Birth outcomes

California Study OP pesticide by products in during DURING pregnancy associated to: Shorter pregnancy – early deliveries Abnormal reflexes at birth Now watching these children’s nervous system as they grow

Summary Long Term Effects of OP’s Length of gestation is shorter in women with higher organophosphate pesticide exposures Newborns of mothers with higher organophosphate pesticide exposures have more abnormal reflexes Pre-natal chlorpyrifos exposure is associated with reduced birth-weight and birth length Children exposed to highest exposures had significantly higher risk of motor and cognitive delay compared to those with lowest exposures Using child behavior checklist, highest exposed group had symptoms of inattentive disorder.

Some Important Facts The younger you are the worse the consequences of OP exposure for development Fetus Soon after birth Nerve system affected Levels so low that they do not inhibit ChE but still effect neural development.

A Women’s Health Project Andhra Pradesh, India

Risks to Children Asthma Brain and kidney tumors Leukemia Neuro-developmental problems Small for age at birth Congenital defects

Health History Interviewing Batambang Province, Cambodia

Neurological and Mental Health Depression, emotional disorders and suicides Earlier poisonings ~ minor depression Canada suicides ~ pesticide use Subtle diminished function of nervous system Occur after severe acute poisonings Chronic low level exposure Parkinson’s Disease [genetics + environmental exposures] Consistent evidence w/ past occupational exposures Mixed pesticides /herbicides investigated

Animal Studies (rodents) Rodents exposed to low levels of OP’s over a long time during pregnancy and right after birth: Problems with gait Tremors Balance problems Run into cliffs Cannot right themselves Eskenazi B. Exposures of children to organophosphate pesticides and their potential adverse health effects. EHP 1999;107 (Suppl 3):409-419

Cancers Brain tumors: 1.7 risk with a dose - response (more pesticide use the higher the risk) 323,292 offspring of Norwegian farmers Breast (?): 1.8 x risk sprayed field, 2.0 x if not use PPE Kidney: children of occupationally exposed men 1.59 x risk. Mortality rate 502 in pentachlorophenol chemical company workers Brain: n=11 [5 cohort +, 5 c/c, 1 eco.] 1.7x risk in children associated to prenatal use of tick –flea products Breast n= 6 [1 cohort, 2 c/c, 3 eco] Cohort:  risk abnormal mammography but n/s for malignancy in greenhouse workers vs non C/C :  risk in veg, fruit and crop farmers . OR 1.8 (1.1-2.8) if in sprayed field 2.0 (1.0-4.3) if did not use PPE but inverse risk with longer duration of farming (re: physical activity, sunlight or anti-estrogenic pesticides?) Eco: # acres ~  risk of B cancer mortality [rice and catfish], Triazine medium exposure 1.14 and high exposure 1.2 Kidney n=6 [2 cohort, 4 c/c] Cohort: 1657,703 kids of occupationally exposed men, PMR 1.59 (1.18-2.15) + pentachlorophenol @ chemical company and death SMR 502 (101-1468) 4 c/c + assoc most consistent for longer duration of exposure and kids of parents occupationally exposed Pancreatic n=3 (2 c/c, 1 cohort) All + especially with high exposure herbicides and fungicides Cohort male aerial pesticides SMR 2.71 (1.4-5.3) ? smoking c/c arsenical OR = 3.4 (.09-12.0) other OR=3.17 (1.1-9.2) job matrix fungicides 1.5 (0.3-7.6) herb 1.6 (0.7-3.4) Non Hodgkin’s Lymphoma n= 27 [cohort 11, c/c 14, Eco 2] 2,4-D implicated previously w/ these studies consistent 23/27 studies show statist sign association w/pesticides and NHL cohort 9/11 + assoc, 3 ss 2 neg c/c 12/14 + assoc, 8 ss, 2 neg eco 2/2 + Source: Sanborn M, Cole D, Kerr K, Vakil C, Sanin LH, Bassil K. Pesticides Literature Review. Ontario College of Family Physicians. Toronto 2004.

Cancers Pancreatic: Aerial applicators (9,961) 2.71x risk than flight instructors (9969) Prostate: 55,322 male applicators 3.75 risk > age 50 with methyl bromide or chlorinated pesticides (organochlorines like DDT or endosulfan) Non Hodgkin’s Lymphoma [Immunologic + environmental factors]: 23/27 studies positive. 2-4 D a precipitant. Leukemia 14/16 studies positive

IPM School Chiang Mai Province, Thailand

Occupational Hazards of Pesticide Studies