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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

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the long term effects of pesticide exposure on human health an update on recent studies
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
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  • What goes unpublished?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
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
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
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
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
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
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
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
Acute Effects
  • What is cholinesterase?
  • Effects of OP’s and Carbamates
  • Organochlorines
  • Pyrethroids
  • Paraquat
slide12

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

slide13

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

slide14

Signs and Symptoms of Acute Organophosphate [OP] Poisoning

e.g. Phorate (Thimet) temephos (Abate), methamidiphos (Monitor)

slide15

Signs and Symptoms of AcuteCarbamate Poisoning

e.g. carbofuran (Furadan) , methomyl (Lannate), thiodicarb (Larvin)

signs and symptoms of acute organochlorine oc poisoning
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
Signs and Symptoms of Pyrethroid Poisoning

e.g. cypermethrin (Raid) , fenvalerlate (Everside) , deltamethrin (Suspend)

paraquat poisoning
Paraquat Poisoning

e.g. “Gramoxone, Parazone, Firestorm ”

skin problems
Skin Problems
  • Skin: Primary exposure route of pesticides
  • Most common effect is contact dermatitis
    • Allergic
    • Irritant
  • 15-25% pesticide illness reports
coexisting factors in agricultural workplace
Plant materials

Solvents

Fuels

Rubber

Cleansers

Creams

Moisture

Cold temperatures

Physical abrasions

Coexisting Factors in Agricultural Workplace
skin problems25
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 ([1997]2): 327–45.

skin problems26
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 problems27
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.

respiratory problems
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 problems30
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
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
Reproductive
  • Menstrual Cycles
  • Birth defects
  • Time to pregnancy
  • Small for Age at Birth
  • Miscarriages
slide33

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
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
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
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
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
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
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
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)

slide42
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 children before during and after organic diet intervention
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
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
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
Health Risks to Children
  • Asthma
  • Cancers
  • Neuro-developmental problems
  • Small for age at birth
  • Congenital defects
asthma
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
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
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
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
new york city cohort study
New York City Cohort Study
  • Fetal exposure to chlorpyrifosis associated with lower birth-weight and birth length
  • Same effect as SMOKING as if the mother was a heavy smoker
  • Abnormal reflexes - OP’s
  • At age 3 those more exposed had delayed movement and mental skills and attention deficits – temporary? *

* Ruah VA. et al. Years of Life Among Inner-City Children Impact of Prenatal 6 on Neurodevelopment in the First 3. Pediatrics 2006;18:1845-1859.

california cohort studies
California Cohort 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 cohort study
California Cohort Study

OP pesticide by-products in urine DURING pregnancy associated to:

  • Shorter pregnancy – early deliveries
  • Abnormal reflexes at birth
  • Neurodevelopmental delays at 6-12-24 months
  • Autism spectrum disorder association to OC’s (endosulfan and dicofol) suggested by a proximity study (<500 meters during pregnancy)

Sources: Young JG et al 2005 and Roberts EM et al 2007

summary of long term neurodevelopmental effects in children
Summary of Long Term Neurodevelopmental Effects in Children
  • Length of gestation is shorter in women with higher organophosphate pesticide exposures
  • Newborns of mothers with higher organophosphate pesticide exposures have 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.
nervous system
Nervous System
  • Mental Health
  • Neurological Symptoms
  • Parkinson’s Disease
mental health
Mental Health
  • Depression, emotional disorders and suicides*
    • Earlier poisonings ~ minor depression
    • Canada suicides ~ pesticide use
  • US Agriculture Health Study – wives of pesticide applicators
    • Self report or MD diagnosed depression in women 3.26 x higher risk if earlier poisoning**

* Sanborn M, Cole D, Kerr K, Vakil C, Sanin LH, Bassil K. Pesticides Literature Review. Ontario College of Family Physicians. Toronto 2004.

** 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.

adult nervous system problems
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*

* Kamel F, et al Neurologic Symptoms in Licensed Private Pesticide Applicators in the Agricultural Health Study. Environ Health Perspect 113:877–882 (2005).

parkinson s and pesticides
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

cancers
Brain Tumors

Breast

Pancreatic

Lymphomas

Leukemia

Kidney

Prostate

Lung

Ovarian

Cancers
brain tumors
Brain Tumors
  • 5 Cohort Studies (all retrospective cohorts) all +
  • Exposure estimations problematic
      • Association membership
      • Pesticide licensees: use or not
      • Pesticide and application equipment purchases*
      • Residence in high pesticide using areas
  • 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.

breast cancer
Breast Cancer
  • 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 unclearrisk* :
    • 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 *
    • p,p´-DDT measured exposure at < age 20

*Engel L, et al (2005). Pesticide Use and Breast Cancer Risk among Farmers’ Wives in the Agricultural Health StudyAmerican Journal of Epidemiology, 161: 121-135.

**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.

other cancers
Other Cancers
  • PancreaticAerial 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.
  • Leukemia14/16 studies positive
  • KidneyIncreased 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.

us agriculture health study cancer outcomes
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
research websites
Research Websites
  • The US Agricultural Health Study

http://aghealth.nci.nih.gov/

  • 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

http://ehs.sph.berkeley.edu/chamacos/

  • The National Children’s Study

http://www.nationalchildrensstudy.gov/

pesticide information websites
Pesticide Information Websites
  • PICOL-Pesticide Information Center On Line WSU

http://picol.cahe.wsu.edu/LabelTolerance.html

  • PAN Pesticides Database:

http://www.pesticideinfo.org/index.htm

  • CDMS Agro Chemical Database

http://www.cdms.net/LabelsMsds/LMDefault.aspx