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Methyl Bromide
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The main points in the comments were the following:
Comment: The
proposed level II REL and toxicologic endpoint for methyl bromide
are based on data that have been found to be inconclusive.
OEHHA’s draft guidelines would establish
a Level II REL of 1 ppm (3.9 mg/m3) and a "reproductive-developmental"
toxicologic endpoint for methyl bromide. The REL apparently is based
on one study, which is identified as Breslin, W.J. et al,
1990. The Methyl bromide Inhalation Teratology Study in New Zealand
White rabbits, Toxicology Research Laboratory, Health and Environmental
Sciences, The Dow Chemical Company Midland, MI, Study No. K-000681-033.
("Breslin Study"). This study purported to establish a
six-hour no observable effect level (NOAEL) of 40 ppm. OEHHA applied
an uncertainty factor of 100 to this NOAEL to generate the proposed
one-hour LEVEL II REL for methyl bromide.
The proposed "developmental-reproductive"
toxicologic endpoint for methyl bromide appears to be based on the
Breslin Study and two additional studies: 1) Sikov et al.
1981. Teratologic Assessment of Butylene Oxide, Styrene Oxide, and
Methyl Bromide. NIOSH Technical Report, Publication no. 81-124,
U. S. GPO (Sikov Study); and 2) Hardin, et al . 1981 . Testing
of Selected Workplace Chemicals for Teratogenic Potential, Scand.
J. Work Environ. Health 4:66-75 (Hardin Study) . As more fully explained
below, the use of the Breslin Study to calculate the REL, and of
all three identified studies as the basis for a "developmental-reproductive"
endpoint designation, is inappropriate.
First, all three studies have been found to be
scientifically insufficient to support the conclusion that methyl
bromide produces developmental toxicity. In 1994, these studies
were specifically evaluated by the California Developmental and
Reproductive Toxicity Committee (DART) and determined to present
inconclusive evidence of developmental or reproductive effects.
Thus, they could not be used as the basis for designating methyl
bromide as a developmental or reproductive toxicant under the Birth
Defects Prevention Act (Proposition 65).
Response: OEHHA
has acknowledged the findings of the DART committee regarding the
Breslin et al. (1990) study. Although there was insufficient
evidence for the DART committee to classify MeBr as a reproductive
toxicant, MeBr still causes serious adverse health effects in animals
in the above studies. We have developed a value for MeBr protective
of those adverse effects, but are not designating the substance
as a reproductive toxicant. The California Proposition 65 qualified
listing of MeBr was that of a reproductive toxicant when used as
a structural fumigant. The DART committee ruling that insufficient
evidence existed to consider methyl bromide a developmental or reproductive
toxicant for the purposes of a full Proposition 65 listing does
not necessarily invalidate the developmental defects in the Breslin
et al. (1990) study, or the maternal CNS effects seen in
the Breslin et al., Hardin et al. (1981), or Sikov
et al. (1981), studies. Similarly, this ruling does not necessarily
contradict the assessments by USEPA or the California Department
of Pesticide Regulation, both of which consider methyl bromide a
reproductive/developmental toxicant.
Comment: The
Sikov Study was deemed inconclusive because the effects were considered
by the authors to be of questionable biological significance. The
Hardin Study was deemed inconclusive due to maternal toxicity, and
the Breslin Study was found to be inconclusive because of the nature
of the effects shown, and the presence of severe maternal toxicity
that likely contributed to several effects purportedly observed
in the offspring.
In light of the Committee’s findings with
respect to the Breslin Study, the 40 ppm NOAEL purportedly established
by this study is unreliable because it is based on equivocal effects.
Thus, it should not be used as the basis for OEHHA’s calculation
of an REL for methyl bromide.
Response:
The adverse effects of methyl bromide on
the test species in the above studies were significant. It is unclear
if the studies have a sufficient basis to consider the compound
a reproductive toxicant for humans. The REL developed is intended
to protect against all serious adverse effects, including those
classified as maternal toxicity. The issue of developmental defects
being secondary to maternal toxicity is therefore immaterial for
the purposes of a severe adverse effect level for methyl bromide,
since both the maternal CNS effects and the adverse developmental
outcomes are serious (severe adverse effect level effects). The
comment acknowledges the severe maternal toxicity seen in each of
these studies. The maternal effects in these studies (including
weight loss, CNS disturbances, and death) were not equivocal, and
should be considered serious by any standard. For this reason, they
formed the basis of the REL developed.
Comment: OEHHA’s
designation of a "developmental/reproductive" toxicologic
endpoint for methyl bromide also is unjustified in light of the
inconclusive nature of all three studies. The Technical Support
Document acknowledges the DART Committee’s conclusion that
these studies are insufficient to support a determination that methyl
bromide is a developmental toxicant yet, despite this acknowledgment,
OEHHA nonetheless concluded that it was appropriate to designate
a "developmental-reproductive" endpoint for methyl bromide.
Absent a complete re-evaluation of all three studies, this is in
direct conflict with the scientific judgment of the DART Committee,
as well as numerous experts in the field of developmental toxicity
that evaluated these studies in the context of the Committee’s
deliberations.
Response:
The criteria for listing a chemical by the
DART committee as "known to the State to cause reproductive
toxicity" require that it clearly be shown that the chemical
causes such toxicity. The DART committee concluded that this strict
standard was not met for methyl bromide. However, other agencies,
such as USEPA and the California Department of Pesticide Regulation
concluded from an extensive evaluation of all the above studies
that methyl bromide caused developmental/reproductive effects in
rabbits and rats, as discussed above.
Comment: An
extensive acute inhalation toxicology database exists for methyl
bromide which provides data consistent with OEHHA’s underlying
intent in determining acute one-hour REL values. Thus, as more fully
explained below, the MBIP believes that OEHHA should revise its
endpoint designation and recalculate the REL using data that has
greater scientific validity.
Response:
The acute inhalation toxicity database for
sub-lethal effects of methyl bromide is not extensive. The only
sub-lethal acute inhalation toxicity data come from unpublished
reports and studies with a small sample size. Virtually no epidemiological
information has been reported regarding acute inhalation of methyl
bromide and reproductive or developmental toxicity in workers.
Comment: The
methodology underlying OEHHA’s REL for methyl bromide is scientifically
flawed because it uses data derived from a repeated-dose study.
In addition to the foregoing, OEHHA’s use
of the Breslin Study is inappropriate for other reasons. The Breslin
study is a repeated-dose study. As more fully explained below, the
use of such studies to calculate a one-hour Level II REL is scientifically
unsound for chemicals such as methyl bromide because the toxicologic
profile from acute exposure to methyl bromide is different from
that produced by repeated exposures.
The MBIP understands that OEHHA’s extrapolation
from six-hour exposure data to an acute one-hour REL is based on
an application of Haber’s law. As a matter of scientific validity,
Haber’s law may be suitable for determination of an acute one-hour
REL by extrapolation from 6-hour acute exposures. However, the use
of Haber’s law with assigned magnitude factors to extrapolate
a one-hour REL from repeated-dose studies is not justified for risk
estimation purposes, especially for chemicals such as methyl bromide.
Studies conducted with methyl bromide in several
animal species, using both single and repeated-dose exposures, clearly
show a steep dose response curve. Repeated-dose studies with methyl
bromide demonstrate that the toxicological effects seen in those
studies are different from those seen in acute studies. Animals
can tolerate acute exposure at high concentrations without effect,
whereas repeated exposures at lower concentrations may produce serious
toxicity.
For example, in a study conducted at the request
of the California Department of Pesticide Regulation (CDPR), daily
repeated exposure (7 hours/day) to a methyl bromide concentration
of 150 ppm (127 mg/kg/day dose equivalent) produced severe neurologic
deficits and abnormality after 5 or 6 exposures. After 1 or 2 exposures
at 150 ppm, the dogs were generally asymptomatic. Similarly, a single
7-hour exposure to a methyl bromide vapor concentration of 233 ppm
was considered a NOEL. When dogs were exposed to 100 ppm (85 mg/kg/day
dose equivalent) on a 7 hour per day, 5 day per week regimen for
4 weeks, no neurological effects nor mortality were seen. These
results clearly demonstrate that the toxicologic profile from an
acute exposure to methyl bromide is different from repeated exposure.
These differences are directly pertinent to the developmental toxicity
data used by OEHHA in its calculations. Developmental toxicity studies
are repeat-exposure studies. In typical studies, pregnant females
are exposed for 10 to 15 consecutive days during gestation. It is
well documented in the literature that developmental toxicants produce
effects at specific critical times during fetal development and
that the effects are chemical specific. Repeated doses are necessary
to assure that a sufficient dose occurs during the critical developmental
stages.
Response: The presentation of the results
of the dog study are in error. As a result of the errors (explained
below) the conclusion regarding single and repeated exposures can
be made from this study. First, the NOAEL for the 7-hour Pharmaco-LSR
study was not 233 ppm as stated in the comment. At this concentration,
dogs were observed to be trembling, panting and blinking rapidly
during exposure. Second, the comment that no neurological effects
were seen following exposure to 100 ppm is also incorrect. At 100
ppm, dogs showed neurological signs (decreased activity, tremors,
and emesis) and decreased body weight gain.
OEHHA acknowledges that the time-extrapolation
from multiple exposures to a 1-hour exposure is not ideal. However,
as indicated in the comment, for a number of substances tested in
developmental toxicity research it has been shown that exposure
to a dose of chemical during a critical period of development can
result in adverse development of the fetus (e.g., in the case of
thalidomide). Thus, unless information to the contrary is available
for the chemical in question, it is prudent to assume that a single
exposure to a teratogen may result in adverse developmental outcome.
Since this is the case and since virtually all available reproductive/developmental
studies are repeated exposure studies (as pointed out by the comment),
a single daily dosage is therefore thought to be sufficient for
the occurrence of developmental toxicity. In the case of methyl
bromide, the comment may be correct that there appears to be a pattern
for cumulative neurotoxicity. The mechanism for this cumulative
neurotoxicity is not known. A thorough evaluation of the Pharmaco-LSR
data by staff from both DPR and OEHHA indicated that 103 ppm was
the highest acute NOAEL in the multi-day study. One dog exposed
to the next higher concentration (156 ppm) experienced lacrimation
after 5 hours exposure. After 3 days exposure to 156 ppm, dogs showed
significant neurological effects.
External peer reviewers, chosen by OEHHA and DPR,
of the Pharmaco-LSR data concluded that time-extrapolation was not
feasible due to the poor quality of the data in terms of sample
sizes and number of independent dose-groups. Therefore, OEHHA proposes
to use the 103 ppm value as an appropriate NOAEL for the purposes
of determining an acute standard. Inclusion of a standard margin
of safety of 100 results in an acute REL of 1 ppm.
Comment: A
single acute dose of a developmental toxicant would not be effective
unless the fetus were in the specific affected period of development
and the appropriate dose were used. Thus, the use of results from
repeated-dose developmental studies as an endpoint for extrapolation
to a one-hour REL constitutes an "apples to oranges" assessment.
In light of the nature of repeated-dose developmental toxicity studies,
the extrapolation should be based on a "precise moment in time"
effect rather than discrete measurable endpoints (such as neurotoxicity,
death, etc.) noted in acute toxicity studies.
Response: The repeated dose studies
resulted in neurotoxicity. The neurotoxic effect of methyl bromide
is not well understood. The extrapolation from repeated exposure
experiments to a 1-hour exposure is more accurate when bioaccumulation
of the chemical or a cumulative effect upon the animal is not present.
However, with methyl bromide, serious neurological effects are seen
after a small number of successive acute episodes in most animals,
even though a one-time exposure does not reveal these effects. The
dose-response slope is clearly very steep in this case and the mechanism
for the cumulative effect is not known. The adequacy of a REL based
on a 1-hour exposure would therefore be dependent upon any prior
exposures to methyl bromide. In practice, the risk assessments for
the Air Toxics Hot Spots program look at one-hour maximum exposures
to compare to the REL. This one hour maximum may occur concomitantly
to other high one-hour exposures slightly below the REL. Methyl
bromide is emitted from Hot Spots facilities. It is entirely plausible
that several one-hour periods of relatively high exposure occur
since meteorological conditions drive the exposures. Repeat exposures
are quite likely for communities near sources of methyl bromide.
The single, acute exposure from the Pharmaco-LSR
study in dogs is now proposed as the new basis for the REL.
Comment: For these reasons, the
MBIP believes that OEHHA should consider other approaches to determining
the one-hour REL for methyl bromide. An appropriate calculation
of the REL is provided below.
The proposed level II REL should be recalculated
using data from the extensive acute inhalation toxicity database
available for methyl bromide.
The MBIP believes that the REL should be recalculated
using data from the extensive acute inhalation toxicology database
that exists for methyl bromide. For the reasons outlined above,
the extrapolation of an acute one-hour REL from an acute 6-hour
exposure is considered an appropriate approach because similar toxic
endpoints are assessed.
Using the results from the acute, single, 7-hour
inhalation exposure in dogs described above, a methyl bromide vapor
concentration of 230 ppm was the No Observable Effect Concentration
(NOEC). This methyl bromide concentration provides a total exposure
dose of approximately 195 mg methyl bromide/kg body weight/day (mg/kg-d)
using respiratory minute volume and standard body weight values
(Biology Data Book, Vol 3 74).
This animal dose permits the calculation of a
human equivalent exposure concentration as follows:
195 mg/kg-d x 24.45/94.95 x 1/0.046 m3/kg-day
= 1091 ppm
*human minute volume = 7.43 1/min
human body weight = 68.5 kg
human exposure 7 hours
As a standard practice (also used by OEHHA in
calculating RELs), a 100-fold factor is used to assess human safety
when extrapolating from animal doses to man. On this basis, a concentration
of 10.91 ppm (1091 ppm/100) would be considered as an acceptable
exposure concentration for man over a 7 hour period. Using a similar
approach to the DOT Criteria above for vapor exposure (2 x the 4-hour
LC50), a 1-hour REL can be calculated as follows:
Adjusted NOEC (7 hours/2) = l-hour REL
1.91 ppm x 3.5 = 38.2 ppm
The MBIP urges OEHHA to recalculate the REL for
methyl bromide using like data for comparative assessments. In order
to calculate an acute 1-hour REL, OEHHA should utilize results from
other acute inhalation tests. As noted above, extensive acute inhalation
toxicity data are available for such purposes. Using the results
from the MBIP’s recent acute inhalation exposure study in dogs,
a l-hour REL of 38.2 ppm would be considered appropriate for methyl
bromide. The MBIP appreciates the opportunity to comment
on OEHHA’s draft risk assessment guidelines and the proposed
REL for methyl bromide. For all the reasons discussed above, the
MBIP urges OEHHA to revise its toxicologic endpoint designation,
and recalculate the REL using data from the extensive acute inhalation
toxicity database that exists for methyl bromide. A more appropriate
calculation would result in a one-hour Level II REL of 38.2 ppm.
Response: Using the data from the
above report, OEHHA has recalculated the REL for methyl bromide
based on severe CNS effects following acute inhalation exposures
in dogs. The methodology presented in the comment (e.g., use of
DOT methods to account for duration of exposure and use of default
breathing rates) is not appropriate for, or consistent with OEHHA’s
Guidelines for the Determination of Acute Toxicity Exposure Levels.
Furthermore, an independent scientific review of the data from the
dog study concluded that time-extrapolation should be avoided for
the purposes of determining an acute REL. Default breathing rates
are often not appropriate since we are concerned about child breathing
rates, not averaged over a day or a lifetime, but which might occur
when a child is outside at play. Finally, as discussed at length
above, 230 ppm is not an appropriate NOAEC for the start of the
calculation. For these reasons, the recalculated severe adverse
effect level for methyl bromide is 1 ppm, not 38.2 ppm. OEHHA found
the comments useful in contributing to the REL generation process.
We have worked with toxicologists from the Department of Pesticide
Regulation and recalculated the REL based on the newer data presented
while being consistent with independent scientific reviewer recommendations
to avoid time-extrapolation when using these data. As a result,
the recommended 1-hour acute REL remains at 1 ppm.
Phenol
Task Group
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The Task Group’s main comments were the following:
Comment: The Task Group urges OEHHA to
revise its risk assessment methodology so that it does not yield
overly conservative values.
Response: The methodology proposed
by OEHHA includes some uncertainty factors to match the data gaps
which are ubiquitous in the toxicological literature. When these
data gaps have been reduced, the magnitude of the uncertainty factors
used for specific chemicals have likewise been reduced. This can
be seen in the benchmark dose calculations, and in many chemicals
where adequate human data exist to characterize practical thresholds
for sensitive individuals. The uncertainty factors in all these
cases were reduced. In this way, the methodology proposed by OEHHA
is responsive to the best scientific information, while safeguarding
public health when significant uncertainties exist.
Comment: Even if OEHHA does not revise
its risk assessment methodology, the Task Group urges OEHHA to maintain
the proposed Level II and Level III values, which are identical
to the AIHA ERPG-2 and ERPG-3 values, respectively.
Response: The AIHA (1992) ERPG-2
and ERPG-3 for phenol were recommended for reevaluation due to serious
errors in the ERPG documentation. The critical concerns with the
ERPG values for phenol are discussed below.
As the basis of the ERPG-2, Flickinger et al.
(1976) was incorrectly cited as reporting a 1-hour exposure to 312 ppm
in rats resulting only in lacrimation. The actual study reports
that slight loss of coordination, in addition to signs of ocular
and nasal irritation, was observed after 4 hours of exposure to
235 ppm. The second key reference for the ERPG-2 is an occupational
report (ACGIH, 1984) of eye, nose, and throat irritation in workers
intermittently exposed to 48 ppm phenol and 8 ppm formaldehyde;
the eye irritation was considered to be caused by the formaldehyde.
However, the ERPG document cites an irritation threshold of 47 ppm
for phenol (Ruth, 1986). This latter finding suggests that the occupational
exposure of 48 ppm phenol actually represents a LOAEL and should
be treated accordingly.
The ERPG-3 was recommended for reevaluation because
the basis for this level was slight loss of coordination and signs
of ocular and nasal irritation observed in rats following a 4-hour
exposure to 235 ppm phenol. The endpoints used are not appropriate
for the development of a life-threatening effect level. As identified
in Table 5 of the Technical Support Document for the Determination
of Acute Toxicity Exposure Levels for Airborne Toxicants, appropriate
effects on which to develop a value for the life-threatening effects
level include severe pulmonary edema, respiratory arrest, ventricular
arrhythmia, cardiac arrest, and death. Therefore, as more appropriate
data become available, it is the intent of OEHHA to revise the existing
severe adverse effect level and life threatening effect level currently
based upon the ERPG-2 and ERPG-3, respectively.
Comment: The Task Group urges OEHHA to
revise upward the proposed Level I (REL) value of 0.038 ppm,
which the Task Group believes is overly conservative and not appropriate
for the purposes stated. The Task group urges OEHHA not to use a
100-fold uncertainty factor for establishing the phenol Level I
(REL) value.
Response: In response to this comment,
OEHHA has revised the REL for phenol, based on the Piotrowski (1971)
human data. The REL has changed from 1.5 x 102 to 5.8
x 103 µg/m³.
Comment: The Task Group urges OEHHA to
consider existing standards for phenol, which are orders of magnitude
different from the proposed Level I (REL) value. Most relevant here
is the AIHA "ERPG-1" value for phenol of 10 ppm.
Response: The ERPG-1 was developed
for rare accidental chemical releases and not the routine exposures
that are being evaluated under the Hot Spots program. Thus, ERPGs
are not appropriate values for RELs. Nonetheless, the ERPG-1 was
evaluated by OEHHA.
The ERPG-1 is based upon a free-standing acute
NOAEL in humans and upon a free-standing chronic NOAEL in rodents.
Of greatest concern to OEHHA was that the ERPG-1 was set approximately
two-fold higher than the reported NOAELs without explanation. While
OEHHA is not averse to using the human free-standing NOAEL reported,
it is not appropriate to use chronic animal data without consideration
of interspecies and exposure duration differences, as is done in
the ERPG-1.
As explained above, the REL for phenol has been
reevaluated using the Piotrowski (1971) human study.
Comment: The Task Group urges OEHHA to
revise its discussion of phenol toxicity data to describe more fully
the existing data.
Response: OEHHA has reviewed its
description of the key studies in question and has supplemented
the descriptions accordingly to reflect comments received. For example,
the chronic toxicity data presented by Sandage (1961) was previously
reviewed by OEHHA and was omitted from the acute toxicity summary
for phenol because the data do not characterize responses to acute
exposure. However, the revision of the acute toxicity summary will
include a description of this chronic animal toxicity data. Also,
the description of the Deichmann (1944) inhalation toxicity study
has been rewritten to emphasize the rat data in order to reflect
comments that, of the species tested, rat metabolism of phenol is
closest to that of humans.
References
American Conference of Governmental Industrial Hygienists (ACGIH).
Documentation of Threshold Limit Values and Biological Exposure
Indices. Cincinnati (OH): ACGIH; 1984.
American Industrial Hygiene Association (AIHA).
Emergency Response Planning Guidelines. Akron (OH): AIHA; 1992.
Flickinger CW. The benzenediols: catechol, resorcinol
and hydroquinone-a review of the industrial toxicology and current
industrial exposure limits. Am Ind Hyg Assoc J 1976;37:596-606.
Piotrowski JK. Evaluation of exposure to phenol:
absorption of phenol vapor in the lungs and through the skin and
excretion of phenol in the urine. Br J Ind Med 1971;28:172-178.
Ruth JH. Odor thresholds and irritation levels
of several chemical substances: a review. Am J Ind Hyg Assoc J 1986;47:A142-A151.
Sandage C. Tolerance criteria for continuous inhalation
exposure to toxic material. I. Effects on animals of 90-day exposure
to phenol, CCl4, and a mixture of indole, skatole, H2S,
and methylmercaptan (ASD Technical Report 61-519). Wright Patterson
Air Force Base (OH): US Air Force Systems Command, Aeronautical
Systems Division; 1961. Available from NTIS, Springfield, VA. NTIS
# AD-268783.
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