study case methyl parathion

8/3/2019 Study Case Methyl Parathion

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IV LATIN AMERICA RISK ASSESSMENT WORKSHOP

STUDY CASEMethyl Parathion: Occupational Exposure

and Risk Assessment

Déborah Mendes Máximo Cardozo

Veterinary

Enviromental Analist

IBAMA

2011



SUMMARY

1.INTRODUCTION.......................................................................................................................1

2.PHYSICAL AND CHEMICAL DATA.......................................................................................1

3.KINECT AND METABOLISM DATA......................................................................................2

3.1 Absorption................................................................................................................................2

3.2 Distribution..............................................................................................................................2

3.3 Metabolism..............................................................................................................................3

3.4 Elimination and Excretion.......................................................................................................3

4.TOXICITY DATA AND TOXICITY EVALUATION................................................................4

4.1 Acute Toxicity..........................................................................................................................4

4.2 Subchronic Toxicity.................................................................................................................4

4.3 Reproductive and Development Toxicity................................................................................4

4.4 Chronic Toxicity/Carcinogenicity...........................................................................................4

4.5 Genotoxicity and Mutagenicity...............................................................................................4

4.6 Immunotoxicity.......................................................................................................................4

4.7 Effects in Humans...................................................................................................................5

5.ECOTOXICOLOGICAL DATA................................................................................................5

6.EXPOSURE...............................................................................................................................6

7.TOXICITY, HARZARD AND RISK ESTIMATION................................................................7

8.RISK EVALUATION.................................................................................................................8

9.CONCLUSION...........................................................................................................................9

10.REFERENCES........................................................................................................................10



Common Name Methyl Parathion

Chemical NameO,O-dimethyl O-p-nitrophenyl

phosphorothioate

Chemical Family Organophosphate

CAS Registry Number 298-00-0

Empirical Formula C8H10O5 NPS

Molecular Weight 263.2 g/mole

Solubility

Solubility in water 55 - 60 mg/l (20°C); soluble

in most organic solvents, slightly soluble in

petroleum and mineral oils

logPow 3 - 3.43

Vapour Pressure 0.41 mPa (25 °C)

Melting Point 35 -36 °C

Reactivity Rapidly hydrolysed in alkaline conditions

3.KINECT AND METABOLISM DATA

Methyl parathion can be readily absorbed by humans following inhalation, oral, or dermal

exposure, although quantitative data are lacking. Studies in animals indicate that oral absorption

following single doses can amount to 80% of the administered dose within a few days of dosing. A

single dermal study in rats also suggested almost complete absorption of an applied dose within a96-hour period. No data are available regarding pulmonary absorption of methyl parathion in

animals.

Methyl parathion has been detected in human breast milk and studies in animals have shown

that it can cross the placenta and be transferred to the fetus. Methyl parathion is rapidly and

extensively metabolized, mainly in the liver, to polar substances that are quickly excreted in the

urine.

Oxidative desulfuration by microsomal oxidases transforms methyl parathion into the

neurotoxic, active metabolite, methyl paraoxon; the specific isozyme involved in this reaction has

not been identified. Other reactions including oxidation, hydrolysis, dearylation, and dealkylation

detoxify methyl parathion. A major detoxification pathway is enzymatic hydrolysis of methyl

paraoxon to dimethyl phosphate and 4-nitrophenol. These metabolites are eliminated primarily inthe urine in humans, rats, and mice.

3.1 Absorption

Often, absorption occurs by multiple routes in humans. Dean et al. (1984) reported deaths

and toxic effects as well as lowered blood cholinesterase levels and excretion of urinary 4-

nitrophenol in several children who were exposed by inhalation, oral, and possibly dermal routes

after the spraying of methyl parathion in a house. In the same incident (Dean et al. 1984),

absorption was indicated in adults who also excreted 4-nitrophenol in the urine, though at lower

levels than some of the children, and in the absence of other evidence of methyl parathion exposure.

In this study, the potential for age-related differences in absorption rates could not be assessed

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because exposure levels were not known and the children may have been more highly exposed than

the adults.

3.2 Distribution

There is limited information available regarding the distribution of methyl parathion after

inhalation exposure in humans or animals. In relation to oral exposure studies, low systemicavailability of methyl parathion following oral gavage in dogs was suggested to be the result of

hepatic first-pass metabolism (Braeckman et al. 1983).

Furthermore, placental transfer of methyl parathion was demonstrated following oral

administration to pregnant rats 1–3 days before parturition. Thirty minutes after administration,

methyl parathion was found in fetal brain, liver, and muscle, and in the placenta and maternal liver,

suggesting its rapid distribution (Ackermann and Engst 1970).

Following single dermal applications of 10 mg/kg of radiolabeled methyl parathion to

pregnant rats, methyl parathion was found to be widely distributed to all major tissues and organs.

Concentrations were highest in plasma and kidney, maximum levels measured 2 hours

postapplication. Peak levels in liver, brain, fetus, and placenta, were measured 2 to 10 hours later, at

which times the highest concentration of methyl parathion was in the fetus (Abu-Quare et al. 2000).

3.3 Metabolism

Methyl parathion is a phosphorothioate, which refers to the organophosphate compounds

that contain the P=S substructure. The low systemic availability of methyl parathion after oral

administration in dogs, and the high hepatic extraction ratios after intravenous administration,

suggest first-pass metabolism by the liver. This compound can be activated (oxidative

desulfuration) to its toxic metabolite, methyl paraoxon. The proposed metabolic pathway is shown

in Figure 1.

Figure 1: Proposed Metabolic Pathways of Methyl Parathion

3.4 Elimination and Excretion

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The available evidence suggests that excretion of methyl parathion metabolites in humansand animals following acute oral exposure is essentially the same and occurs rapidly. Excretion

occurs primarily via the urine and a study in rats also reported excretion of methyl parathion in the

milk (Golubchikov 1991).

Limited information was available regarding excretion in humans and animals after

inhalation exposure.

4.TOXICITY DATA AND TOXICITY EVALUATION

4.1 Acute Toxicity

Methyl parathion is highly toxic via oral and dermal routes. Rats appeared to be the most

sensitive species, among the laboratory animals treated with methyl parathion. In rats, the medianoral lethal doses (LD50) ranged between 6-50 mg/kg (Category I oral toxicant). The dermal rat LD 50

was 67 mg/kg (Category I dermal toxicant), indicating that the toxicity of methyl parathion via oral

route or via skin is comparable. Methyl parathion was classified as Category II inhalation toxicant,

and Category IV eye and skin irritant. An acute (single dose) oral exposure of rats to methyl

parathion caused decreases in the ChE activities in the brain, plasma and erythrocytes, cholinergic

signs, neurobehavioral effects and neuropathology.

4.2 Subchronic Toxicity

Inhibition of the ChE activities in brain, plasma and erythrocytes was the most sensitive

toxicological endpoint after subchronic exposures of rats to methyl parathion by oral and dermal

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routes. Cholinergic signs (including constricted pupils, tremors, gait abnormalities, decreased

activity and abnormal breathing), impairment of the cognitive and motor functions and death were

observed in the oral and dermal studies (5 to 95-day treatment).

4.3 Reproductive and Development Toxicity

The reported effects of methyl parathion on reproduction included: alteration in the levels of the luteinizing hormone in serum and early menopause in humans, decreased pup survival in rats,

possible ovarian toxicity in rats and sperm abnormalities in mice.

Various methyl parathion-induced developmental effects were reported in rats, mice and

rabbits, including lower fetal body weight, increased resorption, reduced pup survival,

abnormalities and variations of ossification and cleft palate.

4.4 Chronic Toxicity/Carcinogenicity

Chronic dietary exposure to methyl parathion of rats produced decreases in the ChE

activities, neurological signs, hematological effects and nerve demyelination. The reduction of the

ChE activity in the mice brain was the most sensitive toxicological endpoint. Methyl parathion wasnot considered to cause cancers in laboratory animals.

4.5 Genotoxicity and Mutagenicity

Methyl parathion was genotoxic in in vitro and in vivo tests causing gene mutations in

bacteria, chromosomal aberrations in mammalian cells, sister chromatid exchange; and was

positive on the sex-linked recessive lethal assay in Drosophila. In vitro, methyl parathion was

shown to bind directly to the cellular DNA.

4.6 Immunotoxicity

Several studies from the open literature showed that methyl parathion has the potential to

alter the immune system. However, further research is needed to clearly identify the health

implications of some of these immunological changes.

The potential for immunotoxicity after long-term exposures was reported by Institoris et al.

(1995) in a 3-generation study in Wistar rats. Methyl parathion at 0, 0.218, 0.291, or 0.436 mg/kg

was administered via intubation, 5 days per week. The effects that were statistically significant

included: decrease in white blood cells, red blood cell, hematocrit, increase in medial red blood cell

cell volume, slight increase in relative liver weight and decrease in relative thymus weight, increase

in the nucleated cell contents in the femoral bone marrow, and dose-dependent decreases in plaque-

forming splenocytes with sheep erythrocytes.

4.7 Effects in Humans

Methyl parathion is a highly toxic pesticide, and humans are susceptible to its acute toxic

effects by various routes of exposure. Signs and symptoms of acute toxicity are typical of those

induced by organophosphate insecticides as a group. Almost all systemic effects of methyl

parathion are related to the action of this compound on the nervous system or are secondary to this

primary action. Methyl parathion and its active metabolite, methyl paraoxon, exert their profound

toxic effect by inhibiting the activity of acetylcholinesterase in the nervous system and at the motor

end-plate. Hydrolysis of acetylcholine is inhibited and the neurotransmitter accumulates at its site of

action, producing overstimulation of cholinergic end organs.

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Information regarding effects in humans is limited to a few case reports of people acutely

exposed to high levels of methyl parathion either by intentional ingestion or by multiple-route

exposure from direct contact with spray material either in field applications or through illegal

indoor spraying. Manifestations of acute poisoning are similar in humans and animals and include

reduced cholinesterase levels in brain, erythrocytes, and plasma, clinical signs of neurological

effects such as tremors and convulsions, and cardiac arrhythmia. Except for neuropsychiatric

disorders reported in humans after chronic occupational exposure to organophosphates includingmethyl parathion, no chronic effects have been documented in humans.

5.ECOTOXICOLOGICAL DATA

Microorganisms can use methyl parathion as a carbon source and studies on a natural

community showed that concentrations of up to 5 mg/litre increased biomass and reproductive

activity. Bacteria and actinomycetes showed a positive effect of methyl parathion while fungi and

yeasts were less able to utilize the compound. A 50% inhibition of growth of a diatom occurred at

about 5 mg/litre. Cell growth of unicellular green algae was reduced by between 25 and 80 µg

methyl parathion/litre. Populations of algae became tolerant after exposure for several weeks.

Methyl parathion is highly toxic for aquatic invertebrates, most LC50s ranging from 1 µg to

about 40 µg/litre. A few arthropod species are less susceptible. The no-observed-effect level for the

water flea (Daphnia magna) is 1.2 µg/litre. Molluscs are much less susceptible with LC50

s ranging

between 12 and 25 mg/litre. Most fish species in both fresh and sea water have LC50

s between 6

and 25 mg/litre, a few species being substantially more or less sensitive to methyl parathion. The

acute toxicity of amphibians is similar to that of fish.

Population effects have been seen in communities of aquatic invertebrates in experimental

ponds treated with methyl parathion. The concentrations needed to cause these effects would occur

only with overspraying of water bodies and, even then, would last for only a short time. Population

effects are, therefore, unlikely to be seen in the field. Kills of aquatic invertebrates would be

unlikely to lead to lasting effects.Care should be taken to avoid the overspraying of ponds, rivers, and lakes, when using

methyl parathion. The compound should never be sprayed in windy conditions. Methyl parathion is

a non-selective insecticide that kills beneficial species as readily as pests. Kills of bees have been

reported following the spraying of methyl parathion. Effects on bees in methyl parathion incidents

were more severe than those of other insecticides. Africanized honey bees are more tolerant of

methyl parathion than European strains. Extreme care must be taken to time methyl parathion

spraying to avoid adverse effects on honey bees.

6.EXPOSURE

Skin absorption, and to a lesser extent inhalation and ingestion, are important routes of

exposure to methyl parathion. Mixers, loaders, flaggers, applicators and field workers are

particularly at risk. Dermal, ocular and inhalation exposure can occur during mixing, loading and

application, cleaning and repair of equipment, and during early reentry in treated areas.

Dermal contact is the predominant route of occupational exposures from the pesticidal use

of methyl parathion. Dermal absorption was evident in the detection of methyl parathion in the

blood, p-nitrophenol in the urine, and ChE inhibition among agricultural workers (Ware et al.,

1974). Without proper respiratory protection, inhalation of methyl parathion can also be a

significant route of occupational exposure. Newell and Dilley (1978) reported that formulating plant

workers protected by respirators had fewer cases of ChE inhibition and poisonings from exposures

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to methyl parathion.

In Brazil this active ingredient is registered to crops of cotton, beans, corn, soybeans and

wheat in formulations as emulsifiable concentrate and microencapsulate with ranges from 400 to

600 g/L a.i. The figure below shows the amount of methyl parathion used in every state of Brazil.

Figure 2: Spatialization of Methyl Parathion sales in Brazil

7.

TOXICITY, HARZARD AND RISK ESTIMATION

The toxicity of methyl parathion is integral to assessing the occupational risk. All risk

calculations are based on the most current toxicity information available for methyl parathion. The

toxicological endpoints, and other factors used in this occupational risk assessments for methyl parathion are listed below.

Harzard Identification

Table 1: Acute Toxicological Categories for Methyl Parathion (Reregistration Eligibility

Decision – RED – for Methyl Parathion by U.S. Environmental Protection Agency)

Study Type Results Toxicity Category

Acute oral (rat) LD50 = 4.5 – 24 mg/kg I

Acute dermal (rat) LD50 = 6 mg/kg I

Acute inhalation (rat) LC50 = < 0.163 mg/L (7mg/kg) I

Primary eye irritation (rabbit) Irritation clear by 7 days III

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Primary skin irritation Max. Score = 2.0; 72 h = 0.5 IV

Dermal sensitization Negative NA

Acute neurotoxicity delayed hen Negative NA

Methyl parathion is very toxic by oral, dermal, and inhalation routes, but is not a strong eye

or dermal irritant and is not a skin sensitizer.

Table 2: Endpoints of Sub-chronic and Chronic Studies (Reregistration Eligibility Decision – RED – for Methyl Parathion by U.S. Environmental Protection Agency)

Exposure Scenario Dose (mg/kg/day) Effect Study

*Short and Intermediate-

term dermal

LOAEL = 0,3Inhibition of brain and

RBC AChE. No NOAEL

identified.

28-Day dermal

toxicity study in rats.

*Short and Intermediated-

term Inhalation

NOAEL = 0,11

Neuropathology and

inhibition of brain,

plasma, and RBC AChE.

Inhalation absorption rate

estimated to be 100%.

One year dietary

neurotoxicity study

in rats.

Cancer Classification: Group “E” or “Not Likely”

*Short- (1 – 30 days) and Intermediate- term (1 – 6 months)

LOAEL = Lowest Observed Adverse Effect Level

NOAEL = No Observed Adverse Effect Level

UF = Uncertainty Factor

RBC = Red Blood Cell

Exposure Assesment

This paper pertains only to the assessment of the occupational exposure to methyl parathion.The human exposure to methyl parathion from occupational activities was expressed as an average

daily dose of exposure (ADD).

ADD = (Unit of exposition) x (aplication rate/frequency) x (ha/day) x (% absorption)

body weight

Handler exposure assessments were completed using a baseline exposure scenario that were

assessed with PHED (Scenarios 28 and 29) and with chemical specific data.

Risk Estimation

Risk for all of potentially exposed populations is measured by a Margin of Exposure (MOE)

which determines how close the occupational or residential exposure comes to a No Observed

Adverse Effect Level (NOAEL). Generally, MOEs greater than 100 do not exceed the risk concern.

The critical NOAELs for characterizing the risk from exposure to methyl parathion were derived

from studies with laboratory animals.

MOE = NOAEL

ADD

Considering that workers are exposed to dermal and inhalation route, the MOE is calculated

like a aggregate Margin of Exposure (MOE):

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MOE total = 1

1 + 1

MOE dermal MOE inhalation

8.RISK EVALUATION

Scenario and Evaluation

The scenario that will analyzed in this section is the exposition of a person mixing, loading

and applying a formulation (emulsifiable concentrate) containing 600 g a.i/L in a soy crop using a

groundboom sprayer with or without Personal Protective Equipment (PPE) .

This situation was selected because parathion methyl is one of the pesticides used to control

insect pests in this important crop in Brazil. The products containing this active ingredient are a

cheap option to producers and because of that they are widely used.

The duration of exposure for handlers of methyl parathion is assumed to be short-and

intermediate-term (1-30 days; 1-6 months). Since methyl parathion is applied to several large

acreage crops (500 until 2.000 ha), it is assumed that a professional pesticide applicator could applymethyl parathion for over one month, then the most important endpoints that will be used are the

relacionated to sub-chronic and chronic studies. Since short- and intermediate-term exposures have

the same endpoints, the following risks are for both durations of exposure. The table 3 summarized

the informations about the scenario described.

Table 3: Scenario Summary

Exposure ScenarioAplication Rate

(kg a.i/ha)Crop

Daily treated area

(ha/day)

Applying liquids with a

groundboom sprayer (ECformulation)

0,6 kg a.i/ha Soy 30

Based on the scenario data, values of the table 2 and the equations (ADD and MOE) the

calculations about occupational risk of methyl parathion were made.

Unit of exposition = 1,9400694 (Dermal)/2,8660117 (Inhalation) – Scenario 28 (No PPE)

0,079366 (Dermal)/2,8660117 (Inhalation) – Scenario 28 (PPE)

0,4850173 (Dermal)/0,7716185 (Inhalation) – Scenario 29 (No PPE)

0,0639341 (Dermal)/0,7716185 (Inhalation) – Scenario 29 (PPE)Rate of application/frequency = 0,6 kg a.i/ha

% Absorption: 100% (1.0 for inhalation) – 100% (1.0 for dermal)

Treated area = 30 ha/day

In this evaluation was considered 100% of dermal absorption because lack of informations

about this parameter in the selected studies. Furthermore, the LOAEL of 0,3 mg/kg/day was divided

by 3 (UF) to extrapolate from a LOAEL to a NOAEL. Then the adjusted NOAEL = 0,1 mg/kg/day.

Dermal and inhalation risks for handlers were combined into a total MOE since the effects

seen at the LOAEL were the same.

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Abu-Qare AW, Abdel-Rahman AA, Kishk AM, et al. 2000. Placental transfer and pharmacokinetics

of a single dermal dose of methyl parathion in rats. Toxicol Sci 53:5-12.

Agency for toxic substances and disease registry (ATSDR) 2001. Toxicological profile for methyl

parathion Atlanta, GA:US. Departament of Healthy and Human Services, Public Healthy Services.

Ackermann H., Engst R. 1970. Presence of organophosphorus insecticides in the fetus. Arch

Toxicol 26:17-22.

Braeckman RA., Audenaert P. Willems J. L., et al. 1983. Toxicokinects of methyl parathion and

parathion in the dog after intravenous and oral administration. Arch Toxicol 54:71-82.

Dean A., Pugh J., Embrey K., et al. 1984. Organophosphate insecticide poisoning among siblings –

Mississipi. MMWR 33:592-594.

Golubchikov MV. 1991. Toxicological substantiation of the safe use of xenobiotics. Gig. San.

(1):56-58.

Guia de Exposição Suplementar do PHED. Estimativas de Exposição Ocupacional - ThePesticide Handler Database Version 1.1. 1998.

Institoris, L., Siroki, O. and Desi, I. 1995. Immunotoxicity study of repeated small doses of

dimethoate and methylparathion administered to rats over three generations. Hum. Experi. Toxicol.

14:879-883.

Newell, G. W. and Dilley, J. V. 1978. Teratology and Acute Toxicology of Selected Chemical

Pesticides Administered by Inhalation. United States Environmental Protection Agency, Office of

Research and Development, Cincinnati, Ohio. Report No. 600/1-78-003, PB277-007.

Ware, G. W., Morgan, D. P., Estesen, B. J. and W. P. Cahill. 1974. Establishment of reentry

intervals for organophosphate-treated cotton fields based on human data. II. Azodrin, ethyl and

methyl parathion. Arch. Environ. Contam. Toxicol. 2:117-129.

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study case methyl parathion

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