327 IAC 2-1.5-14 Determination of human health criteria and values

Sec. 14. (a) This subsection establishes a procedure required when developing Tier I criteria and Tier II values for the protection of human health as follows: (1) The goal of the human health criteria for the Great Lakes system is the protection of humans from unacceptable exposure to toxicants via consumption of contaminated fish and drinking water, and from ingesting water as a result of participation in water-oriented recreational activities. (2) The criteria developed must provide a level of protection likely to be without appreciable risk of carcinogenic or noncarcinogenic effects. Criteria are a function of the level of designated risk or no adverse effect estimation, selection of data, and exposure assumptions. Ambient criteria for single carcinogens must not be set at a level representing a lifetime upper-bound incremental risk greater than one (1) in one hundred thousand (100,000) of developing cancer using the hazard assessment techniques and exposure assumptions described in this subsection. Criteria affording protection from noncarcinogenic effects must be established at levels that, taking into account uncertainties, are considered likely to be without an appreciable risk of adverse human health effects (such as acute, subchronic, and chronic toxicity, including reproductive and developmental effects) during a lifetime of exposure, using the risk assessment techniques and exposure assumptions described in this subsection. (3) Chemical concentration levels in surface water protective of human health must be derived based on either a Tier I or Tier II classification. The two (2) Tiers are primarily distinguished by the amount of toxicity data available for deriving the concentration levels, and the quantity and quality of data on bioaccumulation. (b) The best available toxicity data on the adverse health effects of a chemical and the best data on bioaccumulation factors must be used when developing human health Tier I criteria or Tier II values. The best available toxicity data must include data from well-conducted epidemiologic or animal studies that 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. The information can be obtained from the U.S. EPA Integrated Risk Information System (IRIS) database*, the scientific literature, and other informational databases, studies, or reports containing adverse health effects data of adequate quality for use in this procedure. Strong consideration must 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. When deviations from IRIS are anticipated or considered necessary, actions to address the deviations must be communicated to the U.S. EPA Reference Dose (RfD) or the Cancer Risk Assessment Verification Endeavor (CRAVE) workgroup. The best available bioaccumulation data must include data from field studies and well-conducted laboratory studies as follows: (1) Tier I criteria and Tier II values must be derived using the methodologies described in subsection (c)(1) 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 the U.S. EPA Guidelines for Carcinogen Risk Assessment, (EPA/630/P-03/001F, March 2005, and U.S. EPA 2005 Supplemental Guidance, EPA/630/R-03/00BF, March 2005)**, must be used in determining whether adequate evidence of potential carcinogenic effects exists as follows: (A) Carcinogens are classified, depending on the weight of evidence, as either human carcinogens, probable human carcinogens, or possible human carcinogens. The human evidence is considered inadequate and therefore the chemical cannot be classified as a human carcinogen if one (1) of the two (2) following conditions exists: (i) There are few pertinent data. (ii) The available studies, while showing evidence of association, do not exclude chance, bias, or confounding and therefore a causal interpretation is not credible. The animal evidence is considered inadequate, and therefore the chemical cannot be classified as a probable or possible human carcinogen, when, because of major qualitative or quantitative limitations, the evidence cannot be interpreted as showing either the presence or absence of a carcinogenic effect. (B) Chemicals are described as human carcinogens when there is sufficient evidence from epidemiological studies to support a causal association between exposure to the chemicals and cancer. (C) Chemicals described as probable human carcinogens include chemicals for which the weight of evidence of human carcinogenicity based on epidemiological studies is limited. Limited human evidence is that which indicates that a causal interpretation is credible, but that alternative explanations, such as chance, bias, or confounding, cannot adequately be excluded. Probable human carcinogens are also agents for which there is sufficient evidence from animal studies, and for which there is inadequate evidence or no data from epidemiologic studies as follows: (i) Sufficient animal evidence is provided by data that indicate that there is an increased incidence of malignant tumors or combined malignant and benign tumors: (AA) in multiple species or strains; (BB) in multiple experiments with different routes of administration or using different dose levels, for example; or (CC) to an unusual degree in a single experiment with regard to high incidence, unusual site or type of tumor, or early age at onset. (ii) Additional evidence may be provided by data on dose-response effects, as well as information from short term tests such as mutagenicity and genotoxicity tests that help determine whether the chemical interacts directly with DNA, or on chemical structure, metabolism, or mode of action. (D) Possible human carcinogens are chemicals with limited evidence of carcinogenicity in animals in the absence of human data as follows: (i) Limited animal evidence is defined as data that suggest a carcinogenic effect but are limited because: (AA) the studies involve a single species, strain, or experiment and do not meet criteria for sufficient evidence (see clause (C)); (BB) the experiments are restricted by inadequate dosage levels, inadequate duration of exposure to the agent, inadequate period of follow-up, poor survival, too few animals, or inadequate reporting; or (CC) the studies indicate an increase in the incidence of benign tumors only. (ii) More specifically, this group may include a wide variety of evidence, for example: (AA) a malignant tumor response in a single, well-conducted experiment that does not meet conditions for sufficient evidence; (BB) tumor response of marginal statistical significance in studies having inadequate design or reporting; (CC) benign but not malignant tumors with an agent showing no response in a variety of short term tests for mutagenicity; and (DD) response of marginal statistical significance in a tissue known to have a high or variable background rate. (E) Weight of evidence of potential human carcinogenic effects sufficient to derive a Tier I human cancer criterion (HCC): (i) generally include human carcinogens; (ii) generally include probable human carcinogens; and (iii) may include, on a case-by-case basis, possible human carcinogens if studies have been well-conducted albeit based on limited evidence, when compared to studies used in classifying human and probable human carcinogens. (F) The decision to use data on a possible human carcinogen for deriving Tier I criteria must be a case-by-case determination. In determining whether to derive a Tier I HCC, additional evidence that must be considered includes the following: (i) Available information on mode of action, such as mutagenicity and genotoxicity (determinations of whether the chemical interacts directly with DNA). (ii) Structure activity. (iii) Metabolism. (G) Weight of evidence of possible human carcinogenic effects sufficient to derive a Tier II human cancer value must include those possible human carcinogens 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 dose-response relationship. As with the use of data on possible human carcinogens in developing Tier I criteria, the decision to use data on possible human carcinogens to derive Tier II values must be made on a case-by-case basis. In determining whether to derive Tier II human cancer values, additional evidence that must be considered includes, but is not limited to, the following: (i) Available information on mode of action such as mutagenicity and genotoxicity (determinations of whether the chemical interacts directly with DNA). (ii) Structure activity. (iii) Metabolism. (2) All available toxicity data must be evaluated considering the full range of possible health effects of a chemical, such as 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 and values that will protect against the most sensitive endpoint of toxicity. Although it is desirable to have an extensive database that considers a wide range of possible adverse effects, this type of data exists for a very limited number of chemicals. For many others, there is a range in quality and quantity of data available. To ensure reliability of criteria and values, it is necessary to establish a minimum database with which to develop Tier I criteria or Tier II values. The following represent the minimum data sets necessary for this procedure: (A) The minimum data set sufficient to derive a Tier I HNC must include at least one (1) well-conducted epidemiologic study or animal study. A well-conducted epidemiologic study for a Tier I HNC must quantify the exposure level and demonstrate positive association between exposure to a chemical and an adverse effect in humans. A well-conducted study in animals must demonstrate a dose-response relationship involving one (1) or more critical effects biologically relevant to humans. For example, study results from an animal whose pharmacokinetics and toxicokinetics match those of a human would be considered most biologically relevant. Ideally, the duration of a study should span multiple generations of exposed test species, or at least a major portion of the life span of one (1) generation. This type of data is currently very limited. By the use of uncertainty adjustments, shorter term studies such as ninety (90) 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 Tier I criteria developed pursuant to this procedure, such a limited study must be conducted for at least ninety (90) days in rodents, or ten percent (10%) of the life span of other appropriate test species, and demonstrate a NOAEL. Chronic studies of one (1) year or longer in rodents, or fifty percent (50%) of the life span or greater in other appropriate test species, that demonstrate a 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 (1) or two (2) doses, if the effects observed appear minimal when compared to effect levels observed at higher doses in other studies. (B) 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 with Tier I criteria, all available data must be considered, and ideally should address a range of adverse health effects with exposure over a substantial portion of the life span, or multiple generations, of the test species. When data are lacking, it may be necessary to rely on less extensive data in order to establish a Tier II value. With the use of appropriate uncertainty factors to account for a less extensive database, the minimum data sufficient to derive a Tier II value must include a NOAEL from at least one (1) well-conducted short term repeated dose study. This study must be of at least twenty-eight (28) days duration in animals demonstrating a dose-response, and involving effects biologically relevant to humans. Data from studies of longer duration, greater than twenty-eight (28) days, and LOAELs from these studies may be more appropriate in some cases for derivation of Tier II values. Use of a LOAEL should be based on consideration of the following information: (i) Severity of effect. (ii) Quality of the study. (iii) Duration of the study. (3) The following procedures must be used to determine minimum bioaccumulation data requirements: (A) To be considered a Tier I cancer or noncancer human health criterion, along with satisfying the minimum toxicity data requirements of subdivisions (1)(E) and (2)(A), a chemical must have the following minimum bioaccumulation data: (i) For all organic chemicals either: (AA) a field-measured BAF; (BB) a BAF derived using the BSAF methodology; or (CC) a chemical with a BAF less than one hundred twenty-five (125) regardless of how the BAF was derived. (ii) For all inorganic chemicals, including organometals such as mercury, either: (AA) a field-measured BAF; or (BB) a laboratory-measured BCF. (B) 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 subdivisions (1)(E) and (2)(A) or the minimum bioaccumulation data requirements of clause (A). (c) The fundamental components of the procedure to calculate Tier I criteria or Tier II values are the same. However, certain of the aspects of the procedure designed to account for short duration studies or other limitations in data are more likely to be relevant in deriving Tier II values than Tier I criteria. The following procedures must be used to develop Tier I criteria and Tier II values: (1) The following procedures apply for carcinogens: (A) A nonthreshold mechanism of carcinogenesis must be assumed unless biological data adequately demonstrate the existence of a threshold on a chemical-specific basis. (B) All appropriate human epidemiologic data and animal cancer bioassay data must be considered. Data specific to an environmentally appropriate route of exposure must be used. Oral exposure should be used preferentially over dermal and inhalation since, in most cases, the exposure routes of greatest concern are fish consumption and drinking water/incidental ingestion. The risk associated dose must be set at a level corresponding to an incremental cancer risk of one (1) in one hundred thousand (100,000). If acceptable human epidemiologic data are available for a chemical, it must be used to derive the risk associated dose. If acceptable human epidemiologic data are not available, the risk associated dose must be derived from available animal bioassay data. Data from a species that is considered most biologically relevant to humans, or responds most like humans, is preferred where all other considerations regarding quality of data are equal. In the absence of data to distinguish the most relevant species, data from the most sensitive species tested, that is, the species showing a carcinogenic effect at the lowest administered dose, must generally be used. (C) When animal bioassay data are used and a nonthreshold mechanism of carcinogenicity is assumed, the data are fitted to a linearized multistage computer model. The upper bound ninety-five percent (95%) confidence limit on risk (or the lower ninety-five percent (95%) confidence limit on dose) at the one (1) in one hundred thousand (100,000) risk level must be used to calculate a RAD. Other models, including modifications or variations of the linear multistage model that are more appropriate to the available data, may be used where scientifically justified. (D) If the duration of the study is significantly less than the natural life span of the test animal, the slope may be adjusted on a case-by-case basis to compensate for latent tumors that were not expressed. In the absence of alternative approaches that compensate for study durations significantly less than lifetime, the commissioner may use the process described in the 1980 National Guidelines (see 45 FR 79352). (E) A species scaling factor must be used to account for differences between test species and humans. It must be assumed that milligrams per surface area per day is an equivalent dose between species (U.S. EPA Guidelines for Carcinogen Risk Assessment, EPA/630/P-03/001F, March 2005, and U.S. EPA 2005 Supplemental Guidance, EPA/630/R-03/00BF, March 2005)**. All doses presented in milligram per kilogram body weight will be converted to an equivalent surface area dose by raising the milligram per kilogram dose to the two-thirds (2/3) power. However, if adequate pharmacokinetic and metabolism studies are available, these data may be factored into the adjustment for species differences on a case-by-case basis. (F) Additional data selection and adjustment decisions must also be made in the process of quantifying risk. Consideration must be given to tumor selection for modeling, pooling estimates for multiple tumor types and identifying and combining benign and malignant tumors, for example. All doses must be adjusted to give an average daily dose over the study duration. Adjustments in the rate of tumor response must be made for early mortality in test species. The goodness-of-fit of the model to the data must also be assessed. (G) When a linear, nonthreshold dose response relationship is assumed, the RAD must be calculated using the following equation: RAD = 0.00001 q1* Where: RAD = risk associated dose in milligrams of toxicant per kilogram body weight per day (mg/kg/day). 0.00001 (1 × 10-5) = incremental risk of developing cancer equal to one (1) in one hundred thousand (100,000). q1* = slope factor (mg/kg/day)-1. (H) If human epidemiologic data or other biological animal data indicate that a chemical causes cancer via a threshold mechanism, the risk associated dose may, on a case-by-case basis, be calculated using a method that assumes a threshold mechanism is operative. (2) The following procedures apply for noncarcinogens: (A) Noncarcinogens must generally be assumed to have a threshold dose or concentration below which no adverse effects should be observed. Therefore, the Tier I criterion or Tier II value is the maximum water concentration of a substance at or below which a lifetime exposure from drinking the water, consuming fish caught in the water, and ingesting water as a result of participating in water-related recreation activities is likely to be without appreciable risk of deleterious effects. For some noncarcinogens, there may not be a threshold dose below which no adverse effects should be observed. Chemicals acting as genotoxic teratogens and germline mutagens are thought to possibly produce reproductive or developmental effects via a genetically-linked mechanism which may have no threshold. Other chemicals also may not demonstrate a threshold. Criteria for these types of chemicals will be established on a case-by-case basis using appropriate assumptions reflecting the likelihood that no threshold exists. (B) All appropriate human and animal toxicologic data must be reviewed and evaluated. To the maximum extent possible, data most specific to the environmentally relevant route of exposure must be used. Oral exposure data should be used preferentially over dermal and inhalation since, in most cases, the exposure routes of greatest concern are fish consumption and drinking water/incidental ingestion. When acceptable human data are not available, such as well-conducted epidemiologic studies, animal data from species most biologically relevant to humans must be used. In the absence of data to distinguish the most relevant species, data from the most sensitive animal species tested, such as the species showing a toxic effect at the lowest administered dose (given a relevant route of exposure), should generally be used. (C) Minimum data requirements are specified in subsection (b)(2). The experimental exposure level representing the highest level tested at which no adverse effects were demonstrated (NOAEL) from studies satisfying the provisions of subsection (b)(2) must be used for criteria calculations. In the absence of a NOAEL, the LOAEL from studies satisfying the provisions of subsection (b)(2) may be used if it is based on relatively mild and reversible effects. (D) Uncertainty factors (UFs) must be used to account for the uncertainties in predicting acceptable dose levels for the general human population based upon experimental animal data or limited human data as follows: (i) A UF of ten (10) must generally be used when extrapolating from valid experimental results from studies on prolonged exposure to average healthy humans. This ten (10) fold factor is used to protect sensitive members of the human population. (ii) A UF of one hundred (100) must generally be used when extrapolating from valid results of long term studies on experimental animals, when results of studies of human exposure are not available or are inadequate. In comparison to item (i), this represents an additional ten (10) fold UF in extrapolating data from the average animal to the average human. (iii) A UF of up to one thousand (1,000) must generally be used when extrapolating from animal studies for which the exposure duration is less than chronic, but greater than subchronic, such as ninety (90) days or more in length, or when other significant deficiencies in study quality are present, and when useful long term human data are not available. In comparison to item (ii), this represents an additional UF of up to ten (10) fold for less than chronic, but greater than subchronic, studies. (iv) A UF of up to three thousand (3,000) must generally be used when extrapolating from animal studies for which the exposure duration is less than subchronic, such as twenty-eight (28) days. In comparison to item (ii), this represents an additional UF of up to thirty (30) fold for less than subchronic studies. The level of additional uncertainty applied for less than chronic exposures depends on the duration of the study used relative to the lifetime of the experimental animal. (v) An additional UF of between one (1) and ten (10) may be used when deriving a criterion from a LOAEL. This UF accounts for the lack of an identifiable NOAEL. The level of additional uncertainty applied may depend upon the severity and the incidence of the observed adverse effect. (vi) An additional UF of between one (1) and ten (10) may be applied when there are limited effects data or incomplete subacute or chronic toxicity data, such as reproductive or developmental data. The level of quality and quantity of the experimental data available, as well as structure activity relationships, may be used to determine the factor selected. (vii) When deriving a UF in developing a Tier I criterion or Tier II value, the total uncertainty, as calculated following the procedures in items (i) through (vi) must not exceed ten thousand (10,000) for Tier I criteria and thirty thousand (30,000) for Tier II values. (E) All study results must be converted, as necessary, to the standard unit of milligrams of toxicant per kilogram of body weight per day (mg/kg/day). Doses must be adjusted for continuous exposure, that is, seven (7) days per week, twenty-four (24) hours per day. (F) The RfD must be calculated using the following equation: RfD = NOAEL (or LOAEL) UF Where: RfD = Reference dose in milligrams of toxicant per kilogram body weight per day (mg/kg/day). NOAEL (or LOAEL) = The no observed adverse effect level or lowest observed adverse effect level as determined in accordance with clause (C). UF = The product of the uncertainty factors as determined in accordance with clause (D). (3) The following procedures must be used to derive criteria and values: (A) This subdivision lists the standard exposure assumptions used to calculate Tier I criteria and Tier II values for carcinogens and noncarcinogens. Different levels of exposure may be used where appropriate in deriving site-specific criteria pursuant to section 16 of this rule. The standard exposure assumptions are as follows: (i) BW = Body weight of an average human (BW = 70 kilograms). (ii) WCd = Per capita water consumption, both drinking and incidental exposure, for surface waters classified as public water supplies = two (2) liters per day. (iii) WCr = Per capita incidental daily water ingestion for surface waters not used as human drinking water sources = 0.01 liters per day. (iv) FC = Per capita daily consumption of regionally caught freshwater fish = 0.015 kg/day (0.0036 kilograms per day for trophic level three (3) and 0.0114 kilograms per day for trophic level four (4)). (v) BAF = Bioaccumulation factor for trophic level three (3) and trophic level four (4) as derived using the BAF methodology in section 13 of this rule. (B) The Tier I human cancer criteria or Tier II values must be calculated as follows: Where: HCV = Human cancer value in milligrams per liter (mg/L). RAD = Risk associated dose in milligrams toxicant per kilogram body weight per day (mg/kg/day) that is associated with a lifetime incremental cancer risk equal to one (1) in one hundred thousand (100,000). BW = Weight of an average human (BW = 70 kilograms). WCd = Per capita water consumption, both drinking and incidental exposure, for surface waters classified as public water supplies = two (2) liters per day. WCr = Per capita incidental daily water ingestion for surface waters not used as human drinking water sources = 0.01 liters per day. FCTL3 = Mean consumption of trophic level three (3) of regionally caught freshwater fish = 0.0036 kilograms per day. FCTL4 = Mean consumption of trophic level four (4) of regionally caught freshwater fish = 0.0114 kilograms per day. = Bioaccumulation factor for trophic level three (3) fish as derived using the BAF methodology in section 13 of this rule. = Bioaccumulation factor for trophic level four (4) fish as derived using the BAF methodology in section 13 of this rule. (C) The Tier I human noncancer criteria or Tier II values must be calculated as follows: Where: HNV = Human noncancer value in milligrams per liter (mg/L). RfD = Reference dose in milligrams toxicant per kilogram body weight per day (mg/kg/day). RSC = Relative source contribution factor of eight-tenths (0.8). An RSC derived from actual exposure data may be developed using the methodology outlined by the 1980 National Guidelines (see 45 FR 79354). BW = Weight of an average human (BW = 70 kilograms). WCd = Per capita water consumption, both drinking and incidental exposure, for surface waters classified as public water supplies = two (2) liters per day. WCr = Per capita incidental daily water ingestion for surface waters not used as human drinking water sources = 0.01 liters/day. FCTL3 = Mean consumption of trophic level three (3) fish by regional sport fishers of regionally caught freshwater fish = 0.0036 kilograms per day. FCTL4 = Mean consumption of trophic level four (4) fish by regional sport fishers of regionally caught freshwater fish = 0.0114 kilograms per day. = Human health bioaccumulation factor for edible portion of trophic level three (3) fish as derived using the BAF methodology in section 13 of this rule. = Human health bioaccumulation factor for edible portion of trophic level four (4) fish as derived using the BAF methodology in section 13 of this rule. *This database may be accessed from the U.S. Environmental Protection Agency, IRIS Hotline c/o EPA Docket Center (EPA West, Mail Code 28221T), 1301 Constitution Avenue N.W., Washington, D.C. 20005, or www.epa.gov/iris. **These documents are incorporated by reference. Copies may be obtained from the U.S. Environmental Protection Agency, Office of Water Resource Center (EPA West, Room 1119), 1200 Pennsylvania Avenue, N.W., Washington, D.C. 20460, www.gpo.gov, or are available for review at the Indiana Department of Environmental Management, Office of Legal Counsel, Indiana Government Center North, 100 North Senate Avenue, Thirteenth Floor, Indianapolis, Indiana 46204.