D.  Carcinogenic Effects

Investigators assessed potential carcinogenic effects by calculating a risk (probability) of excess cancer development associated with each relevant pesticide formulation retained, via each route of exposure, based on the medium exposure level, where available, or high exposure level if not. These route-specific risks have also been summed for each POPC for all three routes of exposure within each scenario.

The risk characterization for cancer is determined somewhat differently than that for noncancer effects as there are no specific thresholds for adverse effects. Thus, the following risk range benchmarks have been used here to establish the significance of risk:

These benchmarks were established by analogy with those used by EPA[548] for many years, although EPA does not explicitly refer to "significance" in this context. EPA typically uses these benchmarks in risk management programs throughout the Agency. Normally risks below 1E-06 are considered negligible. Risks between 1E-06 to 1E-04 are frequently, but not always, taken to be "acceptable." Risks greater than 1E-04 typically pose an elevated level of concern.

The route-specific risks and summed scenario-specific risks for application exposure are presented in Table 108. The only risk potentially of concern is that for lindane, at about 3 x 10-4. This is relevant only for the small number of servicemembers who participated in EPW delousing, and is not relevant for the general deployed population. There are relatively few values presented in Table 108 mainly because few of the pesticide active ingredients are associated with carcinogenic effects via the exposure routes of interest, and because only the medium-exposure scenarios are evaluated per OPP guidance (see Section B.4,  Toxicity Assessment).

Table 108. Application risks for evaluation of carcinogenic effects

Formulation

Exposure Level

Route-Specific LADDa
(mg/kg/d)

Riskb
(mg/kg/d)-1

Combination Scenario Riskc

Oral

Dermal

Inhalation

Oral

Dermal

Inhalation

DEET
33% stick/cream
Low

--

--

--

--

--

--

 
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

 
DEET
75% liquid
Low

--

--

--

--

--

--

 
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

 
Permethrin
0.5% aerosol
Low

--

--

--

--

--

--

 
Medium

--

6.46E-08

2.21E-08

--

1.49E-09

3.54E-10

1.84E-09

High

--

--

--

--

--

--

 
d-Phenothrin
2% aerosol
Low

--

--

--

--

--

--

 
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

 
Azamethiphos
1% crystals
Low

--

--

--

--

--

--

 
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

 
Methomyl
1% crystals
Low

--

--

--

--

--

--

 
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

 
Dichlorvos
20% resin strip
Low

--

--

--

--

--

--

 
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

 
Chlorpyrifos
45% liquid (EC) (Handwand Sprayer)
Low

--

--

--

--

--

--

 
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

 
Chlorpyrifos
45% liquid (EC) (Backpack Sprayer)
Low

--

--

--

--

--

--

 
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

 
Diazinon
48% liquid (EC) (Handwand Sprayer)
Low

--

--

--

--

--

--

 
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

 
Diazinon
48% liquid (EC) (Backpack Sprayer)
Low

--

--

--

--

--

--

 
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

 
Malathion
57% liquid (EC) (Handwand Sprayer)
Low

--

--

--

--

--

--

 
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

 
Malathion
57% liquid (EC) (Backpack Sprayer)
Low

--

--

--

--

--

--

 
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

 
Propoxur
14.7% liquid (EC) (Handwand Sprayer)
Low

--

--

--

--

--

--

 
Medium

--

2.57E-07

1.12E-08

--

1.01E-09

4.14E-11

1.05E-09

High

--

--

--

--

--

--

 
Propoxur
14.7% liquid (EC) (Backpack Sprayer)
Low

--

--

--

--

--

--

 
Medium

--

1.49E-06

1.12E-08

--

5.87E-09

4.14E-11

5.91E-09

High

--

--

--

--

--

--

 
Bendiocarb
76% solid (WP)
Low

--

--

--

--

--

--

 
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

 
Chlorpyrifos
19% liquid (ULV)
Low

--

--

--

--

--

--

 
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

 
Malathion
91% liquid (ULV)
Low

--

--

--

--

--

--

 
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

 
Lindane
1% dust
Low

--

--

--

--

--

--

 
Medium

--

1.99E-06

1.46E-05

--

2.22E-06

1.61E-05

2.84E-04

High

2.42E-04

--

--

2.66E-04

--

--

 
a)  LADD = lifetime average daily dose. A dash ("--") indicates that a LADD was not calculated, for one or both of two reasons. First, LADDs were only calculated for chemicals having slope factors. Second, LADDs were calculated for the medium exposure level only, if possible; otherwise, the high exposure level was used. Most of the active ingredients listed are not associated with carcinogenic activity.
b)  Risk = LADD x slope factor. Risks are presented for the oral (risko), dermal (riskd), and inhalation (riski) routes.
c)  Combination scenario risk = risko + riskd + riski. Addends are drawn from low, medium, or high exposure levels, as available.

These findings do not demonstrate that any veteran has or will develop cancer as a result of delousing. According to our investigation, roughly 200 servicemembers were engaged in delousing of EPWs. Based on this, the excess cancer risk for lindane of 3 x 10-4 translates to not even one excess cancer for this group (200 x 3 x 10-4 = 0.06 excess cancers).

The route-specific risks and summed scenario-specific risks for post-application exposure are presented in Table 109. There are no significant risks for post-application exposure. There are relatively few values presented in Table 109 for the same reasons described for Table 108.

Table 109. Post-application risks for evaluation of carcinogenic effects

Formulation

Exposure

Level

Route-Specific LADDa (mg/kg/d)

Riskb (mg/kg/d)-1

Combination Scenario Riskc

Oral

Dermal

Inhalation

Oral

Dermal

Inhalation

DEET
33% stick/cream
Low

--

--

--

--

--

--

  
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

  
DEET
75% liquid
Low

--

--

--

--

--

--

 
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

 
Permethrin
0.5% aerosol
Low

--

--

--

--

--

--

 
Medium

--

5.03E-06

8.36E-06

--

1.16E-07

1.34E-07

2.49E-07

High

--

--

--

--

--

--

 
d-Phenothrin
2% aerosol
Low

--

--

--

--

--

--

 
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

 
Azamethiphos
1% crystals
Low

--

--

--

--

--

--

 
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

 
Methomyl
1% crystals
Low

--

--

--

--

--

--

 
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

 
Dichlorvos
20% resin strip
Low

--

--

--

--

--

--

 
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

 
Chlorpyrifos
45% liquid (EC)
Low

--

--

--

--

--

--

 
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

 
Diazinon
48% liquid (EC)
Low

--

--

--

--

--

--

 
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

 
Malathion
57% liquid (EC)
Low

--

--

--

--

--

--

 
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

 
Propoxur
14.7% liquid (EC)
Low

--

--

--

--

--

--

 
Medium

--

1.14E-04

4.96E-09

--

4.49E-07

1.84E-11

4.49E-07

High

--

--

--

--

--

--

 
Bendiocarb
76% solid (WP)
Low

--

--

--

--

--

--

 
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

 
Chlorpyrifos
19% liquid (ULV)
Low

--

--

--

--

--

--

 
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

 
Malathion
91% liquid (ULV)
Low

--

--

--

--

--

--

 
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

 
Lindane
1% dust
Low

--

--

--

--

--

--

 
Medium

--

--

--

--

--

--

--

High

--

--

--

--

--

--

 
a)  LADD = lifetime average daily dose. A dash ("--") indicates that a LADD was not calculated, for one or both of two reasons. First, LADDs were only calculated for chemicals having slope factors. Second, LADDs were calculated for the medium exposure level only, if possible; otherwise, the high exposure level was used. Most of the active ingredients listed are not associated with carcinogenic activity.
b)  Risk = LADD x slope factor. Risks are presented for the oral (risko), dermal (riskd), and inhalation (riski) routes.
c)  Combination scenario risk = risko + riskd + riski. Addends are drawn from low, medium, or high exposure levels, as available.

E.  Cumulative Hazards and Risks

Tables 110 and 111 present the representative hazard indices (HIs) by branch of service, and the cumulative HIs for organophosphates and carbamates combined. Table 110 presents values for post-application exposure, while Table 111 presents values for applicators (application and post-application exposure). The phrase, "representative hazard index," as used here, means an HI that is potentially relevant to the most servicemembers within each major exposure subdivision (post-application or application). Probably well below 7% of servicemembers who served on the ground in the KTO might have been associated with cumulative HIs for OPs and carbamate approaching those presented in Table 110, and less than 0.2% might have been associated with total HIs for OPs and carbamate approaching those presented in Table 111. Cumulative HIs were compiled as follows:

The criteria for grouping pesticides is fairly straightforward. For post-application exposure, the only difference among the branches has to do with ECs and bendiocarb. The Army did not use much bendiocarb, while the Navy (including Marines) and Air Force did. Since the medium HI for bendiocarb is higher than that for ECs, it was used to represent exposure for the Navy and Air Force in lieu of an EC HI. Conversely, the HI for propoxur was used for the Army in lieu of a bendiocarb HI. Propoxur had the highest medium HI of the ECs. All branches were assumed to be expossed to DEET, permethrin, d-phenothrin, azamethiphos, and dichlorvos. The medium HI for azamethiphos is higher than that for methomyl.

For applicators, the differences have to do with ECs, bendiocarb, and post-application exposure. Again, the bendiocarb medium HI was used for the Navy and Air Force, while an EC medium HI was used for the Army. The EC in the latter case was diazinon, as the HI was higher than for the other ECs. Since applicators would have also experienced post-application exposure similar to non-applicators, post-application exposure is added in.

The rationale for grouping OP and carbamate pesticide formulations together is fully supported by a large body of literature, spanning decades, documenting a common mechanism of action: inhibition of cholinesterase. Details regarding the common mechanism of action are available in many sources, including the RAND pesticides literature review,[549] Ecobichon,[550] and Karczmar.[551] Furthermore, draft policy at EPA's Office of Pesticide Programs (OPP) groups the OPs and carbamates together, and describes the rationale in detail.[552]

The cumulative HIs presented in Table 111 are higher than the comparable values in Table 110, but are potentially relevant mainly to a small subset of servicemembers who applied specific pesticide formulations, such as ECs and bendiocarb WP.

The cumulative HIs listed for OPs and carbamates all exceed 1, and are therefore presumed by investigators to indicate that veterans may have been exposed to levels of pesticide active ingredients capable of causing an identifiable physiological response such as the suppression of plasma cholinesterase. The fact that the HIs not only exceed 1, but significantly exceed one, indicates a relatively greater potential for such a response than if the HIs were closer to or below 1. The HIs for permethrin, d-phenothrin, and lindane, all well below 1, are relatively insignificant in comparison to the cumulative HIs shown for OPs and carbamate.

Cumulative cancer risks were not calculated because it was unnecessary. The cancer risks were insignificant except for application exposure to lindane during EPW delousing, which is relevant only for a specific small subgroup of individuals.

Table 110. Cumulative hazard indices for post-application exposure

Pesticide Group

Formulation

Representative Hazard Indexa

Army Navy Air Force
Repellent(skin) DEET, 33% stick/cream Negligible Negligible Negligible
DEET, 75% liquid
Repellent (clothing) Permethrin, 0.5% aerosol 0.06

0.06

0.06

Area Spray d-Phenothrin, 2% aerosol 0.00014

0.00014

0.00014

Organophosphate
Carbamate

Azamethiphos, 1%

0.001

0.001

0.001

Dichlorvos, 20% resin strip

66

66

66

Propoxur, 14.7% liquid (EC)

0.2

--

--

Bendiocarb, 76% solid (WP)

--

8

8

Chlorpyrifos, 19% liquid (ULV)

0.1

0.1

0.1

Cumulative for OP/Carbamate

67

74

74

a) Based on selected medium scenario-specific HIs. The highest medium HI was selected for each pesticide formulation subgroup (EC/WP or ULV) as representative, based on appropriateness to branch of service. A dash ("--") indicates that either the pesticide formulation was used by 5% or fewer personnel, or that another listed pesticide from the same pesticide formulation subgroup was selected as representative because it was used more frequently and/or had a higher medium HI.

Table 111. Cumulative hazard indices for applicator personnel

Pesticide Group

Formulation

Representative Hazard Indexa

Army

Navy

Air Force

Repellent (skin) DEET, 33% stick/cream Negligible Negligible Negligible
DEET, 75% liquid
Repellent (clothing) Permethrin, 0.5% aerosol

0.06

0.06

0.06

Area Spray d-Phenothrin, 2% aerosol

0.003

0.003

0.003

Lindane Dust Lindane, 5% dust

0.13

0.13

0.13

Organophosphate/
  Carbamate
Azamethiphos, 1%

1.1

1.1

1.1

Diazinon, 48% liquid (EC)

2

--

--

Bendiocarb, 76% solid (WP)

--

17

17

Chlorpyrifos, 19% liquid (ULV)

0.4

0.4

0.4

Post-Application Exposure

67

74

74

Cumulative for OP/Carbamate

71

93

93

a) Based on selected medium scenario-specific HIs. The highest medium HI was selected for each pesticide formulationsubgroup (EC/WP or ULV) as representative, based on appropriateness to branch of service. For permethrin and d-phenothrin, the HI listed is the application plus post-application HI. A dash ("--") indicates that either the pesticide formulation was used by 5% or fewer personnel, or that another listed pesticide formulation from the same formulation subgroup was selected as representative because it was used more frequently and/or had a higher medium HI.

F.  Pesticide Metabolism and Potential Cumulative Effects

Two of the most important determinants of the potential for cumulative effects to occur are whether or not exposures to different chemicals (pesticide active ingredients and daughter products) are "concurrent," and the extent to which binding of the chemical with the critical enzyme acetylcholinesterase is reversible. "Concurrent," as used here, means that active forms of the different chemicals are available in the body at the same time to exert toxic action on the biological target(s), such as cholinesterases. "Reversible," as used here, is a relative term. If the time from initial chemical binding with acetylcholinesterase to regeneration of active enzyme is short, the reaction is said to be reversible. If the time is long, or if no regeneration occurs, the reaction is said to be irreversible. Many, but not all, organophosphate pesticides have the potential to bind irreversibly with acetylcholinesterase, due to a process known as "aging" of the enzyme-pesticide complex. Carbamates bind reversibly. In any case, some nervous system acetylcholinesterase can be inhibited, reversibly or irreversibly, without other observable adverse effects. Beyond a certain point, however, adverse effects will be evident.

All the POPCs are subject to mechanisms in the body which may activate, inactivate and/or otherwise remove them, mainly by metabolism ("biotransformation") and excretion. In general, the body acts to make the chemicals more water-soluble in order to facilitate excretion, and individuals vary widely in their ability to metabolize pesticide active ingredients. Some pesticide active ingredients may undergo a process called "bioactivation" in which a form of the chemical generated in the body is more toxic to the target than the original form of the pesticide active ingredient. The major organ for pesticide active ingredient metabolism is the liver, the site of the highest levels of detoxifying enzyme systems. There is a vast amount of literature on the complicated pathways of pesticide active ingredient metabolism, and it is not feasible to cover the subject in detail here; details are readily available elsewhere.[553] Instead, the following text will address a few additional key points, relying on three important organophosphates (OPs) and one carbamate for illustrative purposes.

Another important consideration of pesticide active ingredient toxicity is its elimination half-life. This is particularly true in the case of repeated exposures. Elimination half-life is the time it takes for the plasma concentration of the pesticide active ingredient to decrease by one-half. Frequently, if the half-life is short in relation to the time between exposures, the pesticide may be almost completely eliminated by the time a subsequent dose is absorbed, and there will be little or no cumulative effect.

More than half of an absorbed dose of chlorpyrifos (an OP) is typically eliminated within 62 hours.[554] Thus, less than 1/8 of the starting dose would typically remain in the body after 8 days. It is safe to conclude that following a single asymptomatic exposure, little of the dose remaining after 8 days would be an active form of chlorpyrifos; most would be in relatively inactive forms. The binding of chlorpyrifos and its bioactivated metabolite chlorpyrifos oxon with cholinesterase can be irreversible.

Inhaled dichlorvos (an OP) is probably absorbed fairly rapidly, although definitive data are lacking.  However, once absorbed, dichlorvos is rapidly broken down and excreted. It is expected that asymptomatic inhalation exposures over the course of several days would be unlikely to lead to detectable levels of dichlorvos in the body within hours of discontinuing exposure. The binding of dichlorvos with cholinesterase is reversible.[555]

Diazinon (an OP) is rapidly broken down and eliminated from the body, and almost all of the dose received during asymptomatic exposure would be eliminated from the body in 12 days. In non-fatal exposures, the effects of diazinon are transient and recovery is rapid and complete following cessation of exposure. The binding of diazinon and its bioactivated metabolite diazoxon with cholinesterase can be irreversible.[556]

Propoxur (a carbamate) is rapidly broken down and excreted. Humans given a single dose of propoxur excreted 38% within 24 hours.[557] Assuming this rate of excretion is constant, about 1/7 of the initial dose should remain after 4 days. Given the rapid metabolism, there should be little active residue left after 4 days. One source stated that no adverse cumulative effects on cholinesterase activity were demonstrated.[558] The binding of propoxur with cholinesterase is reversible.

Thus, sequential asymptomatic exposures to the above pesticide active ingredients, separated by a few days each, are unlikely to contribute to cumulative effects, as manifested by frank effects. Nervous system acetylcholinesterase levels may or may not be reduced in such cases. Conversely, repeated exposures to one or more of the above pesticides occurring within a few hours have the potential to contribute to cumulative effects on nervous system acetylcholinesterase activity. At high enough exposures, frank effects may be evident.

G.  Potential Pesticide Interactions with Pyridostigmine Bromide

Many scientists have expressed concern about the potential for pyridostigmine bromide (PB) to interact with other pesticide active ingredients, particularly organophosphates, carbamates, permethrin, and DEET. At present, there is no evidence that untoward interactions occurred in veterans, only various hypotheses regarding what could have occurred. Thorough discussions of potential PB - pesticide interactions are provided in the RAND literature reviews for PB and pesticides.[559,560]

Potential interaction between PB and pesticide active ingredients may be a concern because:

Several specific items of note are presented in the RAND pesticides literature review. [562] RAND describes studies by Abou-Donia et al. in which adult hens were exposed to the combination of DEET, PB, and either permethrin or chlorpyrifos. The hens exhibited greater than additive effects (not synergistic) when exposed to two of the three compounds, and there was an even greater effect when all three compounds were present. However, given that extremely high doses of some compounds were used, and some were injected, the relevance of these findings to veterans may be limited. The doses used in the hens, if extrapolated to humans, would amount to 467 tablets of PB, 1,667 cans of permethrin, and 76 tubes of 33% DEET. Also, RAND states that, while DEET does not exhibit cholinergic effects, it may enhance the effect of anticholinesterases.

RAND also described a study by McCain et al. which evaluated the lethal action of DEET, PB, and permethrin when given orally to rats via gastric gavage.[563] A gavage is an instrument for delivering a substance directly into the stomach via the esophagus. Again, the combination of compounds produced significantly greater than additive toxicity. Similar to the Abou-Donia et al. studies, extremely high doses and the route of administration limit the relevance. Greater than additive effects from combinations of PB and various pesticide active ingredients were also found in mice and cockroaches.[564] The mouse study utilized intraperitoneal injection to deliver the compounds, while RAND did not report the route of administration for the cockroaches. Thus, relevance remains an issue for the latter two studies due to route of administration. Also, the relevance of a cockroach study is inherently questionable.

It is important to note that the highest levels of pesticide use would not have occurred simultaneously with the highest levels of PB use. In fact, for the majority of personnel, there would have been little if any overlap in exposure. The highest levels of pesticide use, in general, would have been during warm months when the main pest populations were highest; that is, roughly August through November 1990, and March through June 1991. Most servicemembers who took PB would have done so only within the interval of January 17 through February 28, 1991, while offensive operations were in progress. Exposure to pesticides weeks before exposure to PB would be unlikely to produce an adverse interaction. Similarly, exposure to PB at least several days prior to pesticide exposure would be unlikely to produce an adverse interaction.


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