C.  Dose-Response Evaluation

Dose-response evaluation is the process of quantitatively evaluating the toxicity information and characterizing the relationship between the dose of a chemical and the incidence of specific biological effects in the exposed population. Dose-response evaluation as applied here identifies the toxicity values which will be used in risk characterization, and briefly describes the sources of information and how the values were derived. Detailed information regarding derivation of the toxicity values is available in the sources cited, and a broad overview of dose-response for the POPCs may be found in the RAND literature review.[462] The toxicity values are used in the risk characterization step to estimate the likelihood of specific biological effects occurring in humans at the different exposure levels.

Appropriate toxicity values were compiled or extrapolated from published sources. Most of the published values are associated with a medium to high level of confidence; however, one may assume the extrapolated values to be associated with a low level of confidence.

The toxicity values used here are of two types: toxicity values used to evaluate noncarcinogenic effects, and toxicity values used to evaluate carcinogenic effects. In the risk characterization, reference doses (RfDs) are used to evaluate potential noncarcinogenic effects for various exposure durations, as follows:

The exposure durations as defined above are consistent with definitions EPA has used in the past. Recent EPA risk assessments (e.g., for chlorpyrifos[463] ), however, employ a somewhat different convention (not used for the this HRA), as follows: acute (1 day), short-term (1-30 days), intermediate term (30 days to several months), and chronic (several months to lifetime).

Slope factors are used to evaluate potential carcinogenic effects. In some cases where published toxicity values were not available, provisional values were derived by extrapolation as described later.

1.  Noncarcinogenic Effects

For purposes of this HRA two sets of toxicity values are available for the evaluation of noncarcinogenic effects, referred to as follows: "standard toxicity values" (the toxicological approach), and "other human benchmarks" (the epidemiological approach). The standard toxicity values, compiled here, comprise those that have typically been used in conducting quantitative risk assessments for many years. Ideally, the standard values are values verified by EPA, and based on controlled laboratory studies. They are usually based on animal studies, but may be based on human studies. The other human benchmarks, provided in Tab C-8, are not typically used in quantitative risk assessment, but serve a useful role in relation to the HRA. The other benchmarks are based on human studies identified in the literature, such as worker exposure studies.

a. Standard Toxicity Values

Tables 92 through 100 present the standard toxicity values and associated information for the evaluation of noncarcinogenic effects. The tables list the following published values:

The RfD is the key toxicity value which is used in the risk characterization to judge potential noncarcinogenic effects. For each combination of chemical, route, and exposure duration, an RfD has been identified wherever possible and appropriate. In each circumstance, the first value listed (NOEL, NOAEL, or LOEL) is the value upon which the RfD is based. EPA typically takes the most useful "effect level" identified (e.g., NOAEL) and applies a combination of uncertainty and modifying factors to derive the RfD. In most cases listed in Tables 92 through 100, the combined factor ranges between 100 and 300. Given that the RfDs are usually based on some form of no-effect level, they likely err on the side of caution.

An RfD is defined as an estimate (with uncertainty spanning perhaps an order of magnitude) of a daily exposure to the human population (including sensitive subgroups) that is likely to be without appreciable deleterious effects during a lifetime.[464] It is intended to represent the level at or below which adverse (noncancer) health effects would not be anticipated, barring other concurrent exposures and/or compromising factors. Thus, exposure at the RfD for the associated exposure frequency/exposure duration combination (acute/subacute, subchronic, or chronic) should not produce adverse health effects. The converse, however, is not necessarily true; that is, exposure exceeding the RfD does not mean that adverse health effects will occur, although they may. It is true to say that the higher the exposure above the RfD, the greater the likelihood of adverse health effects occurring.

The critical effects listed in Tables 92 through 100 are the toxicity endpoints which provide the basis for each associated toxicity value listed. The most common endpoint listed is cholinesterase (ChE) inhibition. "Cholinesterases," as used here, refers to two enzymes found in animals, including humans: acetylcholinesterase (AChE) and butyrylcholinesterase. The inhibition of the critical enzyme acetylcholinesterase in the central and/or peripheral nervous systems provides direct evidence of potential adverse health effects. However, in the absence of other signs and symptoms, inhibition of nervous system acetylcholinesterase alone is not an adverse health effect. Likewise, inhibition of blood cholinesterases is not itself an adverse effect, although it may indicate a potential for adverse health effects in the nervous system. Red blood cells (RBCs) contain only acetylcholinesterase, while blood plasma contains both butyrylcholinesterase and acetylcholinesterase in varying ratios depending upon species. EPA’s Office of Pesticide Programs (OPP) asserts the following regarding cholinesterase inhibition data: 1) the best data are measurements of acetylcholinesterase inhibition in specific regions of the brain; 2) whole-brain measurements, while potentially useful, may not be sensitive to critical changes in discrete regions; 3) RBC measurements are preferred over plasma measurements; and 4) plasma measurements, despite shortcomings, can be useful in addition to other measurements. For the past several years OPP has required a neurotoxicity screening battery or separate studies for pesticide product registration which characterize the time course of inhibition in plasma, RBCs, and brain, including in specific brain regions, after acute and 90-day exposures. However, existing data sets usually lack the regional brain data.[465]

EPA has identified only chronic oral values for DEET (Table 94). They have not identified any other relevant toxicological endpoints for the quantitative risk assessment of DEET.[466] The EPA has been evaluating DEET extensively over a period of years, and has concluded that DEET insect repellents will generally not cause unreasonable risks to humans when used according to label directions.[467] It has been used by millions of people since first investigated in the 1940s; today approximately 30% of the US population uses DEET annually, and few, if any, adverse health effects can be attributed to its use with any certainty.[468] There is some evidence that DEET may facilitate the absorption of other chemicals such as pyridostigmine bromide (PB);[469] however, typical risk assessment methodology, as used here, is not well suited to addressing this issue. Additional details regarding DEET toxicity are available in the RAND Literature Review.[470]

The RfDs used to evaluate chlorpyrifos were obtained from, or derived based on, a preliminary risk assessment document issued by OPP on October 18, 1999.[471] These values are the most relevant available, since they are based on cholinesterase suppression in adults. OPP has recently identified a more conservative toxicity value known as a population adjusted dose (PAD) for chlorpyrifos incorporating a Food Quality Protection Act (FQPA) factor of 10 for protection of children, embryos, and fetuses.[472] The PAD was not applied in the HRA.

b.  Other Human Benchmarks

Other human benchmarks, supplementing the standard toxicity values, are provided in Tab C-8. These benchmarks are based solely on human studies, and provide another means to characterize the potential hazards associated with the pesticide active ingredient doses estimated in the exposure assessment, although they have not been verified by an outside agency for purposes of risk assessment. Investigators have completed the compilation of benchmarks for the 12 POPC active ingredients. The summary of benchmark values and associated information are presented in Table 104.

The benchmarks presented in Tab C-8 vary widely in terms of reliability for risk assessment purposes. Some of the benchmarks are based on controlled studies with multiple dosing groups and several individuals at each dose level. The doses and timing are certain. In contrast, other benchmarks are based on uncontrolled exposure studies in one or only a few individuals, where doses and timing are estimated but uncertain. The endpoints observed across all benchmarks identified span a wide variety of signs and symptoms, including cholinesterase suppression, mild to moderate frank effects, such as reduction of tendon reflexes, and severe effects, such as coma and death. Investigators identified benchmarks as acute/subacute, subchronic, and chronic, consistent with foregoing portions of the HRA; however, there are many gaps in the literature.

Table 104. Other human benchmarksa

Active Ingredient

Typeb

Human Health Effectsc

Route-Specific Dose [range] mg/kg/day

Source

Oral

Dermal

Inhalation

Multiple
Route

PDR

AD

DEET

A

Unconsciousness, seizures, tremors, epilepticus, lethargy, ataxia, mental confusion, coma.

2.40E+03

Murphy
et al.[473]

S

C

Confusion, abnormal sensation, decreased sweating, muscle cramping, insomnia, irritability, depression, skin rash, blisters.

1.36E+02

Cherniack
et al.[474]
Permethrin

A

Unconsciousness, oral burning sensation, eczema, incoordination, ataxia, hyperactivity, convulsions, cutaneous paresthesia.

1.62E+03

1.78E+01

7.28E-03

Gotoh
et al.[475]; NIOSH[476]

S

C

d-Phenothrin

A

Estimated inhalation NOEL, 24-hour inhalation exposure, typical household spray of d-phenothrin.

1.70E-01

WHO[477]

A

Estimated inhalation NOEL, 1-hour inhalation exposure, typical household spray of d-phenothrin.

7.10E-03

WHO[478]

A

Upper-range dermal human NOEL, treatment of head lice, 1 day.

8.00E-01

1.60E-02

Scott[479]

A

Conservative, lower-range dermal human NOEL, treatment of head lice, 3 days.

4.50E-01

6.00E-03

WHO[480]

S

C

Active Ingredient

Typeb

Human Health Effectsc

Route-Specific Dose [range] mg/kg/day

Source

Oral

Dermal

Inhalation

Multiple
Route

PDR

AD

Azamethiphos

A

S

C

Methomyl

A

Lethal dose was established from food samples containing 12–15 mg/kg methomyl.

1.20E+01

Liddle
et al.[481]

A

Based on qualitative and quantitative methomyl toxicity characteristics, 0.03 mg/kg/day is unlikely to cause adverse effects in humans by any exposure route.

3.00E-02

WHO[482]

A

Intentional ingestion by a woman and child of 13 mg/kg and 55 mg/kg, respectively. Death resulted in both cases.

1.30E+01

WHO[483]

A

A double suicide attempt resulted in one death. An estimated 11 mg methomyl were ingested by the couple. Methomyl powder weighing ~5 g amounts to ~30 mg/kg.

3.00E+01

Miyazaki
et al.[484]

S

C

Dichlorvos

A

LOEL with observed drop in plasma ChE activity from an 8-hour exposure to 1.0 mg/m3.

1.14E-01

Gillett
et al.[485]

A

LOEL for applicators exposed to 0.21 mg/m3 for 25.5 minutes. Applicators had decreased plasma ChE activity.

1.20E-03

EPA[486]

Active Ingredient

Typeb

Human Health Effectsc

Route-Specific Dose [range] mg/kg/day

Source

Oral

Dermal

Inhalation

Multiple
Route

PDR

AD

Dichlorvos

A

Residents exposed to 0.21 mg/m3 for 15.8 hours had decreased plasma ChE activity and headache.

4.70E-02

EPA[487]

S

NOEL from a 14-day exposure to to 0.33 mg/m3.

2.36E–02

Deer

et al.[488]

C

Chlorpyrifos

A

36%–82% plasma ChE inhibition (four people), blurred vision, runny nose, faintness (one person) [Day 9].

1.00E-01

EPA[489]

A

Mean plasma ChE inhibition of 15%. Maximum plasma ChE inhibition of 29% in one individual.

5.00E-01

Nolan
et al.[490]

A

Cyanosis, wheezing, spontaneous voiding of urine and feces, respiratory insufficiency, coma, weakness, paresthesia, reduction of tendon reflexes, reduced sensory and motor nerve conduction, denervation of muscles.

3.00E+02

Lotti
et al.[491]

S

No health effects after 21 days.

3.00E-02

EPA[492]

A

13% mean plasma ChE inhibition.  

5.00E+00

1.20E-01

    Nolan
et al.[493]
Diazinon

A

Significant cholinergic toxic effects, five individuals, recovery after treatment, probable lethality without treatment, upper data point.

9.16E+02

ATSDR[494]

Active Ingredient

Typeb

Human Health Effectsc

Route-Specific Dose [range] mg/kg/day

Source

Oral

Dermal

Inhalation

Multiple
Route

PDR

AD

Diazinon

A

Lethal dose — 54-year old woman; single case.

2.93E+02

ATSDR[495]

A

Significant cholinergic toxic effects, 5 individuals, recovery after treatment, lower data point.

2.40E+02

ATSDR[496]

A

Minimum lethal dose (adult).

5.00E+01

Hayes[497]

A

Plasma AChE LOEL upper range point, no RBC AChE Inhibition, no other physical effects.

5.00E-02

NIOSH[498]

A

Plasma AChE LOEL lower range point, no RBC AChE Inhibition, no other physical effects.

2.00E-02

EPA[499]

A

Plasma AChE NOEL.

2.50E-02

EPA[500]

A

Plasma AChE LOEL upper range point, no RBC AChE Inhibition, no other physical effects.

5.00E-02

NIOSH[501]

S

Plasma AChE LOEL lower range point, no RBC AChE Inhibition, no other physical effects.

2.50E-02

EPA[502]

S

Median low-level no-effects physical or neurobehavioral, occupational, no PPE.

yes

yes

yes

2.80E-04

Maizlish
et al.[503]

Active Ingredient

Typeb

Human Health Effectsc

Route-Specific Dose [range] mg/kg/day

Source

Oral

Dermal

Inhalation

Multiple
Route

PDR

AD

Diazinon

C

Plasma AChE LOEL, no RBC AChE inhibition, no other physical effects.

2.00E-02

EPA[504]
Malathion

A

Lowest published lethal dose for a male.

4.71E+02

NTP[505]

A

Lowest published lethal dose for a female.

2.46E+02

NTP[506]

S

Depression in plasma and RBC ChE activity from 24 mg/day for 56 days.

3.40E-01

EPA[507]

S

NOEL from 16 mg/day for 47 days.

2.30E-01

EPA[508]

C

Propoxur

A

Vomiting, increased blood pressure, sweating, nausea, blurred vision; one individual, single dose; symptoms 30–45 minutes after ingestion, RBC ChE inhibition of 73% returned to normal after 2 hours.

1.50E+00

EPA[509]

A

Stomach discomfort, facial redness, blurred vision, sweating; one individual, single dose; RBC ChE inhibition 43%, returned to normal after 3 hours.

3.60E-01

EPA[510]

A

Transient RBC inhibitions up to 40%, RBC ChE recovery to normal rapid, no other health effects reported, five doses at 30-minute intervals, number of subjects unknown.

2.00E-01

EPA[511]

Active Ingredient

Typeb

Human Health Effectsc

Route-Specific Dose [range] mg/kg/day

Source

Oral

Dermal

Inhalation

Multiple
Route

PDR

AD

Propoxur

A

LOEL (EPA); transient RBC inhibitions up to 40%, RBC ChE recovery to normal rapid, no other health effects reported, five doses at 30-minute intervals, number of subjects unknown.

1.50E-01

EPA[512]

A

NOEL (FAO/WHO); Acceptable Daily Intake (ADI) based on human LOEL of 0.2 mg/kg.

2.00E-02

EPA[513]

A

Human experience, rapid dermal metabolism and animal (rabbit) data.

1.00E+03

EPA[514]

A

LOEL based on 24 workers, 24% erythrocyte AChE inhibition, 53% plasma AChE inhibition; 4-hour exposure at maximum allowable workplace limit; AChE returned to normal at end of 8-hour shift.

6.80E-01

Lewalter
et al.[515]

A

EPA recommended inhalation NOEL for all exposures, NOEL based on animal data included because it is close to human experience LOEL value.

7.50E-01

EPA[516]

S

Acute study, see comment below. LOEL based on 24 workers, 24% erythrocyte AChE inhibition, 53% plasma AChE inhibition, 4-hour exposure at maximum allowable workplace limit, AChE returned to normal at end of 8-hour shift.

6.80E-01

Lewalter
et al.[517]

S

EPA recommended inhalation NOEL for all exposures, NOEL based on animal data included because it is close to human experience LOEL value.

7.50E-01

EPA[518]

Active Ingredient

Typeb

Human Health Effectsc

Route-Specific Dose [range] mg/kg/day

Source

Oral

Dermal

Inhalation

Multiple
Route

PDR

AD

Propoxur

C

Acute study, see comment below. LOEL based on 24 workers, 24% erythrocyte AChE inhibition, 53% plasma AChE inhibition, 4-hour exposure at maximum allowable workplace limit, AChE returned to normal at end of 8-hour shift.

6.80E-01

Lewalter
et al.[519]

C

EPA recommended inhalation NOEL for all exposures, NOEL based on animal data included because it is close to human experience LOEL value.

7.50E-01

EPA[520]
Bendiocarb

A

Exposure effects began at this dose.

1.50E-01

Hayes[521]

A

This dose was followed by mild vertigo, nausea, and sweating. In addition, this dose promoted up to 40% RBC AChE activity.

2.00E-01

Hayes[522]

A

This lowest dose produced no detectable cumulative effects. It is identified as the maximum no-effect level.

1.00E-01

Hayes[523]

A

Lethal dose calculated from a case of self-induced fatal acute poisoning.

5.14E+02

Patel[524]

A

Skin contact failed to produce significant changes in ChE activity.

1.00E-01

Bonsell
et al.[525]; Currie
et al.[526]

A

Skin contact resulted in an asymptomatic but significant decrease in ChE activity of more than 25% from the pre-exposure levels.

3.00E+00

Bonsell[527]; Currie[528]

Active Ingredient

Typeb

Human Health Effectsc

Route-Specific Dose [range] mg/kg/day

Source

Oral

Dermal

Inhalation

Multiple
Route

PDR

AD

Bendiocarb

A

Based on acute oral dose.

1.50E-01

Hayes[529]

S

C

Lindane

A

Lowest lethal dose observed.

1.00E+01

WHO[530]

A

Severe convulsions and liver damage.

3.09E+02

WHO[531]

A

NOEL from a 14-day exposure to 40 mg/day.

5.71E-01

TOXNET[532]

S

C

a) A dash ("—") = specific human health effect not found for the associated route or routes; yes = designation that a multiple route study was used for route.
b) Exposures type: A = acute/subacute; S = subchronic; C = chronic.
c) NOEL = no-observed-effect level; LOEL = lowest-observed-effect level; ChE = cholinesterase; AChE = acetylcholinesterase; RBC = red blood cell; PPE = personal protective equipment; FAO/WHO = Food and Agriculture Organization/World Health Organization.

2.   Carcinogenic Effects

Tables 101 through 103 present the slope factors and associated information for the evaluation of carcinogenic effects. Carcinogenic effects are assessed by application of slope factors (SFs). An SF relates a dose to a probability of excess cancer. In the present case, "excess" cancer refers to cancer hypothetically caused by the exposure to pesticide active ingredients during the Gulf War, as distinguished from cancers due to all other exposures over the course of a lifetime. It should be borne in mind that about 40% of Americans will develop cancer during their lifetimes.[533]

For carcinogens, EPA has developed weight-of-evidence classifications which are reported along with SFs. The weight-of-evidence classification developed by the EPA reflects the likelihood that an agent is a human carcinogen based on available data. There are five groups into which constituents may be classified with regard to carcinogenic potential:

A - Human carcinogen.

B1 or B2 - Probable human carcinogen. B1 indicates that limited human data are available.
        B2 indicates sufficient evidence in animals and inadequate or no evidence in humans.

C - Possible human carcinogen.

D - Not classifiable as to human carcinogenicity.

E - Evidence of noncarcinogenicity for humans.

Occasionally the exact classification is not clear, and the EPA may list a group range, such as "B2/C," meaning that the weight of evidence is not sufficient to place the pesticide active ingredient in one specific group. Also, alternative classifications may be used. For example, lindane is currently listed as B2/C, and OPP states that malathion has "suggestive evidence of carcinogenicity but not sufficient to assess human carcinogenic potential."[534]

3.  Provisional Toxicity Values

The largest number of EPA-verified toxicity values for pesticide active ingredients are for oral exposure, followed by inhalation and dermal exposure. However, where there are no suitable published toxicity values for a given type of exposure, published values for another type may be used as is or modified for use, if appropriate, to generate "provisional" values. For example, EPA has suggested that in some cases it is appropriate to modify an oral reference toxicity value to reflect dermal absorption.[535] All provisional values we used are conservative. The level of confidence in calculated risks based on provisional values is generally lower than with published verified values.

Oral toxicity values are usually presented as administered-dose values. The calculation of hazards and risks via the dermal route, however, requires the use of absorbed-dose values. Therefore, the administered-dose values must be converted to absorbed-dose values. To convert an administered-dose RfD to an absorbed-dose RfD, the administered-dose value must be multiplied by the appropriate oral absorption factor. To convert an administered-dose slope factor to an absorbed-dose slope factor, the administered-dose value must be divided by the appropriate oral absorption factor.

Table 105 presents the oral absorption factors used for the POPCs, taken from the sources listed. The absorption of a pesticide active ingredient through the gastrointestinal tract in either humans or test animals is dependent upon various factors, including the concentration of the pesticide active ingredient, diluent, and the nutritional status of the individual.

Table 105. Oral absorption factors[536]

Active Ingredient

Factora

Source/Rationalea

DEET

--

Extrapolation from oral toxicity value to dermal is inappropriate.
Permethrin

0.70

NRC[537]
d-Phenothrin

0.70

NRC; value for permethrin due to structural similarity
Azamethiphos

1.0

Ciba-Geigy[538]
Methomyl

0.94

HSDB;[539] value for carbaryl used as default for carbamates
Dichlorvos

0.65

ATSDR[540]
Chlorpyrifos

0.90

ATSDR[541]
Diazinon

0.85

ATSDR[542]
Malathion

0.94

HSDB[543]
Propoxur

0.94

HSDB;[544] value for carbaryl used as default for carbamates
Bendiocarb

--

An adequate dermal toxicity value is available.
Lindane

0.99

ATSDR[545]
a) A dash ("--") indicates that an oral absorption factor is not necessary.

In many cases the provisional values listed are simply values published for other exposure conditions. For example, where appropriate, a published chronic value was used as a provisional subchronic value. Since a chronic value is the most conservative, its use as a subchronic or acute/subacute value enhances conservatism. Likewise, in some cases a published oral value was used for an inhalation value. The latter is conservative in the sense that the inhalation route is evaluated, but it may either underestimate or overestimate the true toxicity via inhalation.


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