In the post-application exposure scenarios, the HRA estimated doses were very similar to the levels at which health effects occurred in the research literature. At low exposures, the HRA estimated dose is only 0.25 times the benchmark dose for inhalation exposure. At the medium level exposure, the HRA dose and the benchmark dose are nearly equal, while at the high level exposure the HRA estimated dose is slightly above the benchmark inhalation dose. It should be noted again that the HRA doses were compared with a NOEL from a subchronic inhalation study [Figure 20].

E.  Uncertainty/Variability of this Comparative Risk Characterization

The accuracy of the comparison of HRA doses to benchmark doses in the post-application exposure study is uncertain. The subchronic NOEL (inhalation) dose is higher than the acute LOEL (multiple route) dose. These data were extrapolated from two separate studies that had small test groups.

Based on the published benchmarks at which human health effects occur used in this study, the HRA calculated dose estimates seem to be very close to the doses that cause health effects in humans. However, because this study encompasses only a small amount of benchmark doses for all exposure levels and routes from human health studies, caution should be exercised when comparing human health effects to HRA modeled exposure estimates for this compound.

Figure 20.   Representation of Estimated Risk

1.  Oral Exposure

According to the Agency for Toxic Substances and Disease Registry, "short-term oral exposure (one day) to low (milligrams) levels of chlorpyrifos causes dizziness, runny nose, confusion, salivation, and rapid heart rate. Short-term oral exposure to moderate (grams) levels of chlorpyrifos may cause paralysis, seizures, loss of consciousness, and death. Reports … also show that short-term exposure to chlorpyrifos may cause muscle weakness weeks after the original symptoms have disappeared. This is typical of organophosphate-induced delayed neuropathy (OPIDN). In humans, few cases of true OPIDN have been observed. However, true OPIDN has been seen in laboratory animals following very high doses of the pesticide. No permanent effects of short-term chlorpyrifos exposure in people have been found."^[830]

Two human studies were conducted to determine specific dosages at which human health effects begin to occur. In the first study, by Coulston et al. (1972), male volunteers (4/dose group) were given daily oral doses of 0, 0.014, 0.03, or 0.1 mg chlorpyrifos/kg/d. The initial research protocol proposed that the doses be given for 7 weeks, 9 days, 21 days, and 28 days, respectively. It was reported on Day 9, however, that individuals of the 0.1-mg/kg group reached plasma cholinesterase (ChE) inhibition levels of 36 percent–82 percent and one individual complained of blurred vision, runny nose, and faintness. The report concluded that no significant plasma ChE inhibition was observed in the 0.03-mg/kg group after 21 days or in any of the other test groups. Plasma ChE levels returned to normal 25 days postexposure.^[831]

Human no-observed-effect-levels (NOELs) and lowest-observed-effect-levels (LOELs) for repeated doses were derived from this study and published based on human data.^[832] For plasma ChE inhibition, the NOEL is 0.03 mg/kg/d and the LOEL is 0.1 mg/kg/d. For red blood cell (RBC) acetylcholinesterase (AChE), the NOEL is 0.1 mg/kg/d, but no LOEL could be derived based on available data. There is uncertainty from this study because of the small test population (4 men/dose group) and the wide range of variability observed in the plasma cholinesterase inhibition (36 percent–82 percent in the 0.1-mg/kg/d group). In addition, the investigators attributed the health effects observed in the one individual to common cold, but the US Environmental Protection Agency’s Hazard Identification Assessment Review Committee (HIARC) concluded that a cold could not have caused the blurred vision.^[833]

The second human study, conducted by Nolan et al. (1984), was performed using six Caucasian male volunteers ages 27–50 years. Each volunteer was given a single oral dose of 0.5 mg/kg in pellet form.^[834] The volunteers were subsequently monitored for 30 days to determine plasma ChE and RBC AChE inhibition as well as the chlorpyrifos primary metabolite 3,5,6-trichloro-2-pyridinol (3,5,6-TCP) concentrations in the blood and urine. At no point during the 30 days were any clinical symptoms of toxicity or RBC AChE inhibition observed. Although the original paper reported no RBC AChE inhibition, a later report on the study by the EPA noted that peak AChE inhibition of 11 percent–52 percent was reached on Day 4.^[835] This conclusion seems to be based on a graph presented in the original paper, but the EPA provides no reasoning for the conclusion. To remain consistent with published data, the conclusions made by Nolan et al. (1984) are used in this review. The maximum mean plasma cholinesterase inhibition observed was 15� 1 percent compared with baseline levels. Based on 3,5,6-TCP data, it was estimated that 72� 11 percent of the oral dose was absorbed.

This study, in conjunction with the study mentioned above, led to publication of human NOEL and LOEL data for single-dose exposures.^[836] For plasma ChE inhibition, the NOEL is 0.1 mg/kg and the LOEL is 0.5 mg/kg. For RBC AChE, the NOEL is 0.5 mg/kg. This study is subject to the same uncertainties discussed previously, such as a small test population and variability of observed ChE inhibition among volunteers. This will become increasingly apparent when analyzing the dermal absorption study cited below, which was conducted using the same six volunteers.

Based on the observation of Hayes et al. (1980) that clinical manifestations of acute human toxicity occur when RBC AChE is inhibited at 50 percent of the baseline, an acute oral dose greater that 0.5 mg/kg would be required for adverse health effects.^[837] Unfortunately, there is a lack of data to statistically support this observation. Most reports of chlorpyrifos-induced human toxicity lack dosage data, exposure route information, or discussion of potential contributing factors. Another question arises when referring to the neurological effects reportedly caused by chlorpyrifos and other organophosphate pesticide active ingredients. Investigators in the two human studies did not test for neuropsychological effects, and in cases where clinical tests were run the doses and exposure routes are not available.

OPIDN is associated with exposure to a few specific organophosphates, possibly including chlorpyrifos at very high doses. This syndrome is caused by the inhibition of neurotoxicity target esterase (NTE) in neural tissue, which triggers the degradation in sensory and motor axons of the peripheral nerves and/or spinal chord.^[838] The inhibition of NTE occurs within hours of intoxication, and OPIDN has only been reported in cases where the dose was extremely high.^[839]

In one reported case, a 42-year old male ingested ~300mg/kg chlorpyrifos in an attempted suicide.^[840] Plasma cholinesterase activity measured 36 hours postexposure was nearly zero and the individual remained comatose with cholinergic symptoms for 17 days. Day 30 measurements of RBC and plasma cholinesterase as well as NTE were all significantly below normal levels, but began to rise from that point on. "On Day 43, the patient complained of weakness and paresthesias in the legs and symmetrical reduction of tendon reflexes was noted. Sensory conduction velocity was reduced and signs of denervation of some muscles [were] recorded. On Day 62, the leg weakness was more severe, the patient showed some gait impairment, and the tendon reflexes were absent. On electomyograph, the muscles of the legs showed symmetrical signs of denervation with signs of spontaneous activity." Further examination showed reduction of motor and sensory conduction velocities as well as signs of axon and myelin degeneration. Other cases of attempted suicide and accidental chlorpyrifos exposures with similar symptoms have been reported, but definitive doses are not provided.^[841]

2.  Dermal Exposure

Nolan et al. (1984) conducted a human dermal absorption study in connection with the oral study mentioned above, using the same six volunteers.^[842] One received two 0.5 mg/kg dermal doses, one dissolved in methylene chloride and the other in dipropylene glycol methyl ether [DPGME], and the remaining five received doses of 5.0 mg/kg dissolved in DPGME. It was determined that 1.35� 1 percent of the dermal dose was absorbed based on blood chlorpyrifos measurements following exposure. The mean plasma ChE inhibition in the five volunteers was 13 percent, but further analysis showed a large discrepancy in levels between individuals. A 20 percent decrease was observed in one individual; there was no decrease in levels for two of the volunteers and a high variability in levels for the other two volunteers.

Based on the information from this study, if one were to assume that a maximum of 2.35 percent of the 5.0 mg/kg dermal dose was absorbed, that would give an absorbed dose of approximately 0.12 mg/kg. This 0.12 mg/kg dose could be the assumed absorbed human acute dermal LOEL even though two of the individuals showed no plasma ChE inhibition at this dose.

3.  Inhalation Exposure

Fenske et al. (1990) performed measurements to determine the maximum air concentration of chlorpyrifos following residential broadcast applications.^[843] Samples were taken from both ventilated and nonventilated rooms. Wipe samples taken within 0.5 hours following application were 1.69 �g/cm² and 3.90 �g/cm² in the ventilated and nonventilated rooms, respectively. Chlorpyrifos vapors measured 100 cm above the carpet never exceeded 20 �g/m³ in ventilated rooms, and maximum levels greater than 60 �g/m³ were measured in nonventilated rooms.

A poison control center report on chlorpyrifos exposures over a 10-year period provides four fatalities potentially caused by inhalation of high levels of chlorpyrifos.^[844] Two separate exposures occurred in adult males while spraying chlorpyrifos under houses. Both experienced cardiopulmonary arrest that resulted in their deaths. No other causal factors are suggested and no dose estimates were provided. For these and other reasons, it is difficult to make conclusions with respect to these cases.

A third exposure occurred when, "an 85-year-old male was admitted to the hospital for treatment of pneumonia and sepsis." He had symptoms of lethargy, diarrhea, and fever. Four days before he was hospitalized, his home had been treated with a chlorpyrifos containing compound. One-week post application, soil samples taken from under the house contained 560 ppm chlorpyrifos and the air-conditioning filter contained 46 ppm. When the house was swabbed, chlorpyrifos levels were measured at 170 �g/ft². His vital signs upon hospital admission were: heart rate 100 beats per minute; blood pressure 122/50 mmHg; temperature 99.6�F; and "rales were ausculated over the lungs." The patient died 13 days after being admitted to the hospital. Caution should be exercised when drawing conclusions from this case study because of the lack of a definitive dose, the age of the victim, and uncertainty of exposure route.

The fourth fatality occurred when a 39-year-old female inhaled an entire aerosol can containing chlorpyrifos, hydrocarbons, and pyrethrins. Her symptoms included cardiac arrest en route to the hospital, multiple seizures, neuromuscular abnormalities, and excessive pulmonary secretions. She died 16 days postexposure. Among the difficulties in drawing conclusions from this case study are lack of dose information, concentration of chlorpyrifos, and the presence of hydrocarbons and pyrethrins in the insecticide mixture.

Because of a lack of dose response data in humans for acute inhalation exposure, we will assume for the purpose of this review that equivalent absorption would occur in both oral and inhalation routes, and use the acute oral LOEL of 0.1 mg/kg/d for Health Risk Assessment (HRA) comparison.

B.  Subchronic Health Effects

1.  Oral Exposure

Two human studies were conducted to determine specific dosages where human health effects begin to occur. In the first study, male volunteers (4/dose group) were given daily oral doses of 0, 0.014, 0.03, or 0.1 mg chlorpyrifos/kg/d.^[845] The initial research protocol proposed that the doses be given for 7 weeks, 9 days, 21 days, and 28 days, respectively. However, on Day 9, individuals of the 0.1-mg/kg group reached plasma ChE inhibition levels of 36–82 percent and one individual complained of blurred vision, runny nose, and faintness. The report concluded that no significant plasma ChE inhibition was observed in the 0.03-mg/kg group after 21 days or in any of the other test groups. Plasma ChE levels returned to normal 25 days postexposure.

From this study, human NOELs and LOELs for repeated doses were derived and published.^[846] For plasma ChE inhibition, the NOEL is 0.03 mg/kg/d and the LOEL is 0.1 mg/kg/d. For RBC AChE, the NOEL is 0.1 mg/kg/d, but no LOEL could be derived based on the available data. There is uncertainty in this study because of the small test population (4 men/dose group) and the wide range of variability observed in the plasma cholinesterase inhibition (36–82 percent in the 0.1-mg/kg/d group). In addition, the investigators attributed the health effects observed in the one individual to a common cold, but the HIARC concluded that a cold could not have caused the blurred vision.^[847]

2.  Dermal Exposure

Human health effects studies providing toxicology benchmark dosages for this exposure route were not found in the research literature. For this reason, the data from the acute dermal human studies will be used to make subchronic comparisons to the HRA exposure estimates. 

3.  Inhalation Exposure

Because of a lack of dose response data for subchronic inhalation exposure, we will assume for the purpose of this review that equivalent absorption would occur in both oral and inhalation routes and use the subchronic oral NOEL of 0.03 mg/kg/d for HRA comparison.

C.  Chronic Health Effects

1.  Oral Exposure

For the purpose of this report, it will be assumed that the subchronic data collected from the human study reported above will remain constant and will be used in the HRA comparison.

2.  Dermal Exposure

Human health effects studies providing toxicology benchmark dosages for this exposure route were not found in the research literature. For this reason, the data from the acute dermal human studies will be used for making chronic comparisons to the HRA exposure estimates.

3.  Inhalation Exposure

Because of a lack of dose response data for chronic inhalation exposure, we will assume for the purpose of this review that equivalent absorption would occur in both oral and inhalation routes and use the subchronic oral NOEL of 0.03 mg/kg/d for HRA comparison.

D.  Risk Characterization: Comparison of HRA-Modeled Dose Estimates to Non-Carcinogenic Health Effects

Please refer to the reference table(s) in Section B.4.C.1.b of Other Toxicity Benchmarks from Human Data.

Table 149. Chlorpyrifos, comparison of HRA doses to benchmarks (application exposure)