(B)
Minimum data requirements. The best available toxicity data on the adverse
health effects of a chemical and the best data on bioaccumulation factors shall
be used when developing human health tier I criteria or tier II values
as follows:
The best available toxicity data
includes data from well-conducted epidemiologic or animal studies which
provide, in the case of carcinogens, an adequate weight of evidence of
potential human carcinogenicity and, in the case of noncarcinogens, a
dose-response relationship involving critical effects biologically relevant to
humans.
Such data is obtained from the U.S. EPA
integrated risk information system (IRIS) database, scientific literature, and
other informational databases, studies and reports containing adverse health
effects data of adequate quality for use in this rule, when available. Strong
consideration shall be given to the most currently available guidance provided
by IRIS in deriving criteria or values, supplemented with any recent data not
incorporated into IRIS.
The best available bioaccumulation data
includes data from field studies and well-conducted laboratory
studies.
(1) Carcinogens.
(a) Tier I human cancer criteria (HCC) and
tier II human cancer values (HCV) shall be derived using the methodologies
described in paragraph (C)(1) of this rule when there is adequate evidence of
potential human carcinogenic effects for a chemical. The U.S. EPA
classification system for chemical carcinogens, which is described in
"Guidelines for Carcinogen Risk Assessment, Risk Assessment Forum, U.S.
Environmental Protection Agency" shall be used in determining whether adequate
evidence of potential carcinogenic effects exists. Carcinogens are classified,
depending on the weight of evidence, as carcinogenic to humans, likely to be
carcinogenic to humans, or having suggestive evidence of carcinogenic
potential. The human evidence
is considered inadequate and therefore the
chemical cannot be classified as a human carcinogen, if any of the following
conditions exists:
(i) There is little or no
pertinent information.
(ii) Some
studies provide evidence of carcinogenicity but other studies of equal quality
with animals of the same sex and strain are negative.
(iii) There are negative results that are not
sufficiently robust for the descriptor "not likely to be carcinogenic to
humans."
(iv) There is animal
evidence that demonstrates lack of carcinogenic effect in both sexes in
well-designed and well-conducted studies in at least two appropriate animal
species (in the absence of other animal or human data suggesting a potential
for cancer effects).
(v) There is
convincing and extensive experimental evidence showing that the only
carcinogenic effects observed in animals are not relevant to humans.
(vi) There is convincing evidence that
carcinogenic effects are not likely by a particular exposure route.
(vii) There is convincing evidence that
carcinogenic effects are not likely below a defined dose range.
(b) Chemicals are described as
"carcinogenic to humans" when either: there is convincing epidemiological
evidence of a causal association between human exposure and cancer; or when all
of the following conditions are met:
(i) There
is strong evidence of an association between human exposure and either cancer
or the key precursor events of a chemical's mode of action but not enough for a
causal association.
(ii) There is
extensive evidence of carcinogenicity in animals.
(iii) The mode or modes of carcinogenic
action and associated precursor events have been identified in
animals.
(iv) There is strong
evidence that the key precursor events that precede the cancer response in
animals are anticipated to occur in humans and progress to tumors, based on
biological information.
(c) Chemicals described as "likely to be
carcinogenic to humans" include chemicals for which the weight of evidence is
adequate to demonstrate carcinogenic potential to humans but does not reach the
weight of evidence for the descriptor "carcinogenic to humans." Chemicals with
weight of evidence demonstrating carcinogenic potential to humans can include,
but are not limited to the following:
(i) Chemicals for which a plausible
association is demonstrated between human exposure and cancer, in most cases
with some supporting biological, experimental evidence, though not necessarily
carcinogenicity data from animal experiments.
(ii) Chemicals that tested positive for
carcinogenicity in animal experiments in more than one species, sex, strain,
site, or exposure route, with or without evidence of carcinogenicity in
humans.
(iii) Chemicals for which
positive tumor study results are demonstrated that raise additional biological
concerns beyond that of a statistically significant result, for example, a high
degree of malignancy or an early age of onset.
(iv) Chemicals for which a rare animal tumor
response in a single experiment is demonstrated that is assumed to be relevant
to humans.
(v) Chemicals for which
positive tumor study results are demonstrated that are strengthened by other
lines of evidence, for example, either plausible association between human
exposure and cancer or evidence that the chemical or an important metabolite
causes events generally known to be associated with tumor formation likely to
be related to tumor response in this case.
(d) "Suggestive evidence of carcinogenic
potential" is evidence used to describe chemicals where the weight of evidence
is suggestive of carcinogenicity; a concern for potential carcinogenic effects
in humans is raised, but the data are judged not sufficient for a stronger
conclusion. Chemicals with weight of evidence suggestive of carcinogenicity can
include, but are not limited to the following:
(i) Chemicals with studies that show a small,
and possibly not statistically significant, increase in tumor incidence
observed in a single animal or human study that does not reach the weight of
evidence for the descriptor "likely to be carcinogenic to humans."
(ii) Chemicals with studies that show a small
increase in a tumor with a high background rate in that sex and strain, when
there is some but insufficient evidence that the observed tumors may be due to
intrinsic factors that cause background tumors and not to the chemical being
assessed.
(iii) Chemicals with
evidence of a positive response in a study whose power, design, or conduct
limits the ability to draw a confident conclusion, but where the carcinogenic
potential is strengthened by other lines of evidence.
(iv) Chemicals with studies that show a
statistically significant increase at one dose only, but no significant
response at the other doses and no overall trend.
(e)
Development
of Tier I criteria.
Chemicals
with the necessary weight of evidence of potential human carcinogenic
effects sufficient to derive a HCC
generally include chemicals that are carcinogenic to humans and likely to be
carcinogenic to humans.
Such
chemicals can also include, on a
case-by-case basis as determined by the director, chemicals with suggestive
evidence of carcinogenic potential if studies have been well-conducted when
compared to studies used in classifying chemicals that are carcinogenic to
humans or likely to be carcinogenic to humans. The decision to use data
from a
chemical
that
has suggestive evidence of carcinogenic potential for deriving tier I
criteria
is a case-by-case determination.
In determining whether to derive
a HCC, additional evidence that shall be considered includes but is not limited
to available information on mode of action, such as mutagenicity/genotoxicity
(determinations of whether the chemical interacts directly with DNA), structure
activity, and metabolism.
(f)
Development
of Tier II value.
Chemicals
with the necessary weight of evidence of effects suggestive of carcinogenic
potential sufficient to derive a HCV shall include those chemicals with
suggestive evidence of carcinogenic potential for which there are, at a
minimum, data sufficient for quantitative risk assessment, but for which data
are inadequate for tier I criterion development due to a tumor response of
marginal statistical significance or inability to derive a strong doseresponse
relationship. In determining whether to derive tier II human cancer values,
additional evidence that shall be considered includes but is not limited to
available information on mode of action such as mutagenicity/genotoxicity
(determinations of whether the chemical interacts directly with DNA), structure
activity and metabolism.
The decision to use data
on chemicals with suggestive evidence of carcinogenic potential to derive tier
II values
is made on a case-by-case basis by the
director.
(2)
Noncarcinogens.
(a) All available toxicity
data shall be evaluated considering the full range of possible health effects
of a chemical, i.e., acute/subacute, chronic/subchronic and
reproductive/developmental effects, in order to best describe the dose-response
relationship of the chemical, and to calculate human noncancer criteria (HNC)
and human noncancer values (HNV) which will protect against the most sensitive
endpoint of toxicity. Paragraphs (B)(2)(b) and (B)(2)(c) of this rule provide
the minimum data sets necessary to calculate HNC and HNV,
respectively.
(b) Tier I. The
minimum data set sufficient to derive an HNC shall include at least one
well-conducted epidemiologic study or animal study
which meets the following
requirements:
(i)
A
well-conducted epidemiologic study for an HNC
quantifies exposure level and
demonstrates positive association between exposure to
a chemical and adverse effect in humans.
(ii)
A well-conducted
study in animals demonstrates a dose response relationship involving one or
more critical effect biologically relevant to humans. The duration of a study
should span multiple generations of exposed test species or at least a major
portion of the lifespan of one generation. By the use of uncertainty
adjustments, shorter term studies (such as ninety-day subchronic studies) with
evaluation of more limited effect may be used to extrapolate to longer
exposures or to account for a variety of adverse effects. For an HNC developed
pursuant to this rule, such a limited study must be conducted for at least
ninety days in rodents or ten per cent of the lifespan of other appropriate
test species and demonstrate a no observable adverse effect level (NOAEL).
Chronic studies of one year or longer in rodents or fifty per cent of the
lifespan or greater in other appropriate test species that demonstrate a lowest
observable adverse effect level (LOAEL) may be sufficient for use in tier I
criterion derivation if the effects observed at the LOAEL were relatively mild
and reversible as compared to effects at higher doses. This does not preclude
the use of a LOAEL from a study (of chronic duration) with only one or two
doses if the effects observed appear minimal when compared to effect levels
observed at higher doses in other studies.
(c) Tier II. When the minimum data for
deriving tier I criteria are not available to meet the tier I data
requirements, a more limited database may be considered for deriving tier II
values
as
follows:
(i)
As with
tier I criteria, all available data shall be considered and shall address a
range of adverse health effects with exposure over a substantial portion of the
lifespan (or multiple generations) of the test species.
(ii)
With the use of appropriate uncertainty factors to
account for a less extensive database, the minimum data sufficient to derive a
tier II value shall include a NOAEL from at least one well-conducted short-term
repeated dose study. This study is of at least twentyeight days duration, in
animals demonstrating a dose-response, and involving effects biologically
relevant to humans.
(iii)
Data from studies of longer duration (greater than
twenty-eight days) and LOAELS from such studies (greater than twenty-eight
days) may be more appropriate in some cases for derivation of tier II values.
Use of a LOAEL is based on consideration of the following information: severity
of effect, quality of the study and duration of the study.
(3) Bioaccumulation
factors (BAFs).
(a) Tier I for carcinogens and
noncarcinogens. To be considered a tier I cancer or noncancer human health
criterion, along with satisfying the minimum toxicity data requirements of
paragraphs (B)(1) and (B)(2) of this rule, a chemical shall have the following
minimum bioaccumulation data. For all organic chemicals either: A
field-measured BAF; a BAF derived using the biota-sediment accumulation factor ( BSAF) methodology; or a BAF less than one hundred
twenty-five regardless of how the BAF was derived. For all inorganic chemicals,
including organometals such as mercury, either: a field-measured BAF; or a
laboratory-measured BCF.
(b) Tier
II for carcinogens and noncarcinogens: a chemical is considered a tier II
cancer or noncancer human health value if it does not meet either the minimum
toxicity data requirements of paragraph (B)(1) or (B)(2) of this rule or the
minimum bioaccumulation data requirements of paragraph (B)(3)(a) of this
rule.