Why it is inappropriate for epa to remove the intraspecies uncertainty factor for chloropicrin



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Why it is inappropriate for EPA to remove the intraspecies uncertainty factor for chloropicrin

Variability even among the human test subjects is greater than a factor of 10


In Table 1A, Appendix A, p. 78 (relevant part reproduced below) of the Human Health Risk Assessment for chloropicrin, eye irritation thresholds were found to vary by greater than a factor of 10 between study participants. Note that the final “acceptable” acute concentration of 73 ppb is twice the concentration that the 10th percentile subject responded to.


Effect

Threshold conc.
10th percentile
(most sensitive subjects)


Threshold conc.
90th percentile
(least sensitive subjects)


Threshold conc.
median


(average subject)

Factor by which 10th percentile differs from 90th percentile

Eye irritation

37 ppb

1,565 ppb

242 ppb

42

Odor

216 ppb

764 ppb

406 ppb

1.9



Appendix A/Table 1A: Chloropicrin Toxicity Profile

Guideline No./Study Type

MRID No. (year)/Classification/Exposure Conditions

Results

Special Human Study: Odor Threshold, Nose, Eye, Throat Irritation

46443801 (2004)

Acceptable/Non-Guideline

3 Phases

Phase 1: 62 subjects (356, 533, 800, and 1200 ppb) for 1-2 seconds from a vapor delivery devise

Phase 2: 62 subjects (0, 50, 75, 100, 150 ppb) for 30 minutes in a walk-in chamber

Phase 3: 32 subjects (100, 150 ppb) for 60 mins/day for 4 consecutive days in a walk-in chamber


Phase I:

Registrant Analysis:

median odor threshold: 700 ppb; (M=590 ppb and F=810 ppb)

median eye irritation: 900 ppb; (M=790 ppb and F=1010 ppb)

No localization of the throat; >1200ppb

HED Analysis:

Odor: 10th percentile 216 ppb; median 406 ppb; 90th 764 ppb

Eye: 10th percentile 37 ppb; median 242 ppb; 90th 1565 ppb


Phase 2: 38% of subjects (8M/8F) detected chloropicrin initially at 50 ppb and consistently up to 150 ppb. Severity of eye irritation not examined. NOAEL not determined. Nose and throat irritation not as sensitive as in eyes.
Phase 3: NOAEL not established. However, BMCL10 of 73 ppb, based on eye irritation scores of 1.5 during the maximal response period of 30-55 minutes. Nasal nitric oxide increased and changes in air flow both at 100 ppb and 150 ppb. Nose and throat irritation less sensitive endpoints.



Members of the Human Subjects Review Board Recommended that Additional Uncertainty Factors Beyond the Intraspecies Uncertainty Factor Be Used


From the July 25, 2006 Minutes of the United States Environmental Protection Agency (EPA) Human Studies Review Board (HSRB), June 27-30, 2006 Public Meeting, Docket Number: EPA-HQ-ORD-2006-0384
p. 5: Summary of the study: “During Phase 1, the duration of exposure for odor detection was 1-2 seconds, eyes were exposed for 25 seconds, and nose irritation exposures lasted 7 seconds in one nostril. Some subjects could not detect chloropicrin at the levels tested. Overall strengths of the study included the determination of pertinent odor and eye thresholds with similar responses among males and females. Phase 2 was conducted in a walk-in chamber. Severity of feel was not a parameter in Phase 2. Subjects were asked to make a confidence of response judgment. The walk in chamber was considered a more appropriate exposure scenario for acute bystander exposure. For all phases, the doses were low to high and included both sexes. For Phases 1 and 2 there were no severity scores, no physiological parameters, and the durations of exposure were not equal. Phase 3 was designed for occupational exposure and was also conducted in the walk- in chamber. Exposure duration was 60 minutes/day for 4 days. Phase 3 included clinical examination of the eyes, nose and throat, before, during and after exposure. Perceptual effects, the time required to feel irritation, decreased with increasing concentration. Study strengths included subjective and objective measures and repeated dosing. Study weakness included lower concentrations, as studied in Phase 2, and not being examined (i.e. 100 ppb) in Phase 3.
Dr. Reaves concluded that Phase 3 provided physiological parameters for eye irritation and was used as the point of departure (POD) for chloropicrin. The BMDL10 of 73 ppb was based on eye irritation noted during Phase 3.”
p. 5: “The Board began its initial discussion questioning the lack of confidence intervals.”
p. 6: “Dr. Lebowitz stressed that you cannot estimate inhalation risk from any other route of exposure besides inhalation exposure. Dr. Fenske followed by clarifying that in Phase 2, there were 20-30 minute exposure intervals. He was concerned that a lower dose was not included in Phase 3 given the results of Phase 2 at the lower dose. Dr. Reaves clarified that for Phase 2, there was no measure of the severity of effects. Dr. Brimijoin asked how the Agency intended to address acute versus chronic effects since the human studies all dealt with short-term exposure. Dr. Reaves said that the animal data would be used to assess chronic effects but chronic exposures were not expected given chloropicrin’s use as a soil fumigant.”
p. 8: Some subjects did respond at the lowest dose (50ppb).
p. 8: “Phase 3 investigated eye, nose and throat irritation for several days. One limitation was no lower dose level. By selecting healthy subjects, subjects with existing inflammation were excluded. The study included good subjective and objective measures of exposure and reasonable statistical analysis. Consecutive exposures did not seem to matter since there was no day-to-day increase in response. Most of the standards were plus or minus 3% of the measure and no lower airway effects were noted. The nasal passage cytology did not show significant irritation. Dr. Lebowitz concluded that the study was reasonably sound from a scientific perspective but he did not think the most sensitive subjects were included.”
p. 8: “Dr. Fisher summarized the Board findings as follows: the study was well-designed and provided information on acute exposure and interspecies variability. There was Board concern about the lack of one-to-one correspondence with the levels used in Phase 2 and Phase 3. The study did provide useful information for occupational exposures. The study may be used for bystander populations but consideration should be given to the fact that bystander populations may include more sensitive individuals.”

From US EPA’s DER


p. 3: For example, as a group, subjects differentiated 50 ppb chloropicrin in the eyes from the blank after 20 minutes of exposure. Differentiation from blank occurred after 5 minutes at 75 ppb, 3 minutes at 100 ppb, and 2 minutes at 150 ppb. There was no significant interaction with sex for the eyes, nose, or throat.
p. 5: “On an individual level, the severity of ocular irritation reported by subjects in Phase III varied from no symptoms to severe at both 100 ppb and 150 ppb. 5 of 17 females (29%) and 7 of 15 males (47%) rated no eye irritation at 100 ppb while 3 of 17 females (18%) and 5 of 15 males (33%) rated no eye irritation at 150 ppb. Nasal and throat irritation was never reported above a “2" and mainly consisted of “0" or “1". Scores of severe “3" ocular irritation were sporadic during the first 30 minutes of exposure in 2 females and in 4 males at 100 ppb. The second half of the exposure to 100 ppb (31-60 minutes) revealed a more consistent response in ocular severity (3 females, 5 males). Severe was defined as “symptom hard to tolerate and can interfere with activities of daily living or sleeping”. At 150 ppb, 4 females and 3 males reported consistent severe eye irritation beginning as early as 8 to 9 minutes of exposure until the end of exposure at 60 minutes.”
p. 7: In Phase III where the lowest dose tested was 100 ppb, “The LOAEL is 100 ppb, the lowest concentration tested, based on eye irritation, increased nasal nitric oxide (nNO), and differential effect on inspiratory and expiratory flow. A NOAEL was not established in Phase III. . . In summary, the concentrations and durations explored in each of the three Phases of this study failed to identify a level at which none of the subjects responded to either irritation or odor of chloropicrin.”
p. 10: On screening of subjects: Only subjects who reported, inter alia, no smoking within a year, no use of recreational drugs within a year, no recent illness, and no history of chronic illness qualified to go on to screening in the laboratory. The only question that subjects could answer “yes” and still remain in consideration for inclusion concerned allergies.
An examination of the nose, throat, and eyes was performed for each participant with any irritation, abnormalities, or abnormal redness scored on 0-3, with a score greater than 1 grounds for exclusion of the study. The examination also included measurement of nasal resistance (Rhino; MultiSpiro or HR-Rhinomanometry) and pulmonary function (MultiSPIRO SX-SILVER). Cells were also taken from the surface of the inferior turbinate of one nasal cavity via a Rhinoprobe scraping.
Criteria for passing screening included the following (pg 42 of final report):

1. On olfactory functioning: identification of 5 or more of test odors of the Connecticut Chemosensory Clinical Research Center Test for odor identification.

2. On clinical exam: Absence of pathology and, in particular, of signs greater than mild.

3. On cytological grounds: Absence of ciliocytophthoria (clumping of chromatin) in epithelial cells as evidence for viral infection, absence of large numbers of neutrophils with intracellular bacteria as evidence of bacterial infection, and absence of large numbers of eosinophils or basophilic cells as evidence of inflammation, all defined by standard criteria.

4. For nasal airway resistance: Absence of clinically abnormal resistance, defined as >5 cm H20/L/sec for the nostrils combined, a clinical criterion.

5. For pulmonary function testing: pulmonary function at or above 83% of predicted forced expiratory volume at 1 sec (FEV1) or forced vital capacity (FVC) for testing by ATS criteria.




Rationalization that children don’t need additional protection


  • Second, the incident reports for chloropicrin do not suggest that individuals with asthma are more sensitive to chloropicrin. In addition, these incident reports suggest that children are as responsive to chloropicrin as adults.

From the incident reports (pp. 4-5):

“II. Poison Control Center Data - 1993 through 2001

Results for the years 1993 through 2001 are presented below for occupational and non-occupational reports involving adults and older children. There were insufficient numbers for children under age six to warrant a detailed analysis. Cases involving exposures to multiple products or unrelated outcome are excluded.”


Distances at which effects were noted:

Incident report, p. 9: More than one mile away, 5-8% of the 190 adults interviewed



reported possible symptoms.
Incident report, p. 9: Residents that lived about one-quarter mile from the land reported irritant symptoms that evening. . . . A retrospective air dispersion model estimated exposures of 0.20 ppm with peak concentrations estimated above 1 ppm. As a result of this incident, the County Agricultural Commissioner prohibited applications within one-quarter mile of occupied structures and mandatory use of a heavy-duty tarp or water seal for applications within one-half mile of such structures.
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