Assessment of potential risk levels associated with U.S. Environmental Protection Agency reference values.

The U.S. Environmental Protection Agency (U.S. EPA) generally uses reference doses (RfDs) or reference concentrations (RfCs) to assess risks from exposure to toxic substances for noncancer health end points. RfDs and RfCs are supposed to represent lifetime inhalation or ingestion exposure with minimal appreciable risk, but they do not indude information about the estimated risk from exposures equal to the RfD/RfC. We used results from benchmark dose modeling approaches recently adopted for use in developing RfDs/RfCs to estimate the risk levels associated with exposures at the RfD/RfC. We searched the U.S. EPA Integrated Risk Information System (IRIS) database and identified 11 chemicals with oral RiDs and 12 chemicals with inhalation RfCs that used benchmark dose modeling. For assessments with sufficient model information, we found that 16 of 21 (76%) of the dose-response models were linear or supralinear. We estimated the risk from exposures at the established RfDs and RfCs for these chemicals using a linear dose--response curve to characterize risk below the observed data. Risk estimates ranged from 1 in 10,000 to 5 in 1,000 for exposures at the RfDs, and from I in 10,000 to 3 in 1,000 for exposures at the RfCs. Risk estimates for exposures at the RfD/RfC values derived from sublinear dose--response curves ranged from 3 in 1,000,000,000 to 8 in 10,000. Twenty-four percent of reference values corresponded to estimated risk levels greater than 1 in 1,000; 10 of 14 assessments had points of departure greater than the no-observed-adverse-effect levels. For policy development regarding management of cancer risks, the U.S. EPA often uses 1 in 1,000,000 as a de minimis risk level. Although noncancer outcomes may in some instances be reversible and considered less severe than cancer, our findings call into question the assumption that established RfD and RfC values represent negligibly small risk levels. Key words: benchmark dose, noncancer, risk assessment. Environ Health Perspect 111:1318-1325 (2003). doi:10.1289/ehp.6185 available via http://dx.doi.org/ [Online 12 May 2003]

**********

Methods for evaluating risks from exposure to toxic substances for noncancer health end points (such as birth defects, respiratory effects, and hepatotoxicity) are based on the theory that there is a threshold below which there is negligible risk of adverse health effects from environmental exposures. At the U.S. Environmental Protection Agency (U.S. EPA), this negligible risk is quantified through the use of reference doses (RfDs) and reference concentrations (RfCs). The RfD or RfC is defined as an estimate of daily or continuous exposure to the human population (including sensitive subgroups) that is likely to be without an appreciable risk of deleterious effects during a lifetime (U.S. EPA 1999a). The value of the RfD or RfC is derived by determining a point of departure divided by uncertainty factors (UFs), which are used to account for uncertainties in the available studies, such as limitations in the database, variability within humans, and differences in species response (i.e., animal-to-human extrapolation).

The point of departure in environmental health risk assessment is meant to represent the lowest dose within the range of experimental data. In past practices, the point of departure was exclusively based on a no-observed-adverse-effect level (NOAEL) or a lowest-observed-adverse-affect level (LOAEL), derived from animal or epidemiologic studies. The NOAEL is the highest dose for which there are no observed statistically or biologically significant increases in the frequency or severity of adverse effects between the exposed population and its control. Similarly, the LOAEL is the lowest dose at which there are statistically or biologically significant increases in the frequency or severity of adverse effects between the exposed population and its appropriate control group. The NOAEL/LOAEL structure, however, does not provide sufficient information to quantify the equivalent risk levels from exposure at the RfD/RfC because there is no estimated risk at the NOAEL or LOAEL itself. Several authors have criticized the use of the NOAEL because of its sensitivity to sample size, the high sampling variability from experiment to experiment, and the inability to use all of the available dose-response data (Barnes et al. 1995; Crump 1984; Gaylor et al. 1998; Leisenring and Ryan 1992; U.S. EPA 2000a). Leisenring and Ryan (1992) have shown that average risk levels associated with the NOAEL may be substantial. The true risk of exposure at the NOAEL can vary from zero to > 20%, depending on the end point, spacing of doses, and numbers of animals used (Leisenring and Ryan 1992). In many cases, an adverse effect may not be detected in a critical effect study because of insufficient statistical power.

Although the NOAEL/LOAEL structure does not provide sufficient information to quantify risk levels from exposure (Gaylor and Kodell 2000), the resulting RfDs and RfCs are assumed to be equivalent to negligible or de minimis risks. As a point of comparison, the U.S. EPA has defined 1 in 1,000,000 excess cancer risk as a de minimis risk level for cancer (Caldwell et al. 1998; Clean Air Act Amendments 1990; Fiori and Meyerhoff 2002; U.S. EPA 1991), although regulatory actions are sometimes limited to instances where risk exceeds 1 in 100,000.

Over the past several years, the U.S. EPA has been in the process of developing the benchmark dose (BMD), which is derived from modeling the exposure-response data, as an alternative to the NOAEL/LOAEL as the point of departure for noncancer risk assessments. The BMD is the dose that corresponds to a specified level of increased response [the benchmark response (BMR)] compared with background. This dose is calculated by fitting a mathematical model to the dose--response data, which can be continuous or quantal. The BMD method has several advantages over the NOAEL/LOAEL method, including making better use of dose-response information and reflecting sample size more appropriately (Barnes et al. 1995; Crump 1995). In single--chemical hazard assessments, the BMD allows for consideration of the dose--response over the entire exposure range, and furthermore, when a dose derived from benchmark modeling is used as the point of departure, actual risk levels can be calculated as an alternative to the hazard index (which is typically based on comparisons of human exposures with an RfD or RFC).

In 2000, the U.S. EPA published a draft guidance document on the application of the BMD approach in determining the point of departure for all types of health effects data (U.S. EPA 2000a). Although a BMR of 10% has most often been used by the U.S. EPA in its assessments, it is anticipated that 5% or 1% would be a more appropriate response level for some end points and designs. Furthermore, in these draft guidelines, a lower statistical confidence limit on the BMD (BMDL) is specifically proposed as a replacement for the NOAEL/LOAEL in setting the point of departure, which is used to determine acceptable levels of human exposure to environmental toxicants. A lower confidence limit is placed on the BMD to obtain a dose (BMDL) that assures with high confidence (e.g., 95%) that the BMR is not exceeded (U.S. EPA 2000a). In addition to ensuring an added measure of protection, this process rewards better experimental design and procedures that provide more precise estimates of the BMD.

Most new and revised RfDs and RfCs in the U.S. EPA Integrated Risk Information System (IRIS) assessments are based on BMD modeling. Certain health end points, however, are not amenable to modeling, and the NOAEL/LOAEL approach will continue to be used in some cases (U.S. EPA 2000a). For this article, we have reviewed and synthesized currently available risk assessment information on the chemicals for which U.S. EPA reference values are based on BMD modeling. We estimate the equivalent risk levels expected from hypothetical human exposures at established RfD and RfC values using the BMD dose--response information to investigate whether these levels represent negligible risks, and to underscore some of the potential strengths of using benchmark modeling in environmental health risk assessment.

Methods

We searched the U.S. EPA IRIS database (U.S. EPA 2000b) to identify the chemicals for which current regulatory reference values relied on BMD modeling. We identified 11 chemicals with RfDs based on oral BMD values, and 12 chemicals with RfCs based on benchmark concentration (BMC) values. The BMD and

BMC values and other risk assessment information for these chemicals are presented in Tables 1-4 (U.S. EPA 1995a, 1995b, 1995c, 1995d, 1997a, 1998a, 1998c, 1998e, 1998g, 1999b, 2000c, 200la, 200lb, 2001d, 2002a, 2002c, 2002e, 2003). We have included risk assessment information for naphthalene, a chemical with an IRIS assessment containing an established RfD based on a NOAEL (RfD = 0.02 mg/kg/day) as well as a prospective RfD based on BMD modeling (RfD = 0.03 mg/kg/day) (U.& EPA 1998i).

We determined whether the principal study identified for each chemical's IRIS assessment was derived from quantal (dichotomous) or continuous critical effect data (Tables 2 and 4). For compounds with BMD or BMC values based on quantal data, the BMR is expressed in terms of a percent increase in risk of adverse outcome compared with background. For compounds with BMD or BMC values based on continuous data, the BMR may be expressed as a percent change in mean response compared with control (e.g., immunosuppression with tributyltin oxide) or in terms of a 1 standard deviation change from the control mean response (e.g., decreased lymphocyte count with benzene). The BMR is a response level used to define a BMD, which is used as the point of departure, from which an RfD or RfC can be developed. The BMR is typically set at the lower end of the range of responses (e.g., 10% or 5% change) that can be detected experimentally. This can help to avoid uncertainties associated with low-dose extrapolation using models that may not reflect biologic realities (Crump 1995).

Using the benchmark modeling information described above from the IRIS assessments of 19 chemicals, we estimated the equivalent risk levels expected from hypothetical human exposures at the established RfDs and RfCs. We also evaluated whether each of the models used for BMD calculations was linear, sublinear, or supralinear in the observed dose range (Table 5) [National Research Council (NRC) 2000; U.S. EPA 1995a, 1995b, 1995c, 1995d, 1997b, 1998b, 1998c, 1998d, 1998f, 1998h, 1998j, 1999c, 2000d, 2001c, 2001e, 2002b, 2002d]). To estimate the risk level of the derived IL/Ds and RfCs, which have a linear or supralinear dose--response curve at the BMD/BMC, we assumed that the dose--response curves for these compounds are linear at doses below the BMD or BMC (Figure 1). For two assessments, sufficient information was not available td determine the shape of the dose--response curve (carbon disulfide and 1,1,1,2-tetrafluoroethane), and we assumed linearity [this assumption did not overly bias our results because linearity or supralinearity was the shape of the dose--response curve in approximately three-quarters (16 o.f.21) of cases in which the shape of the dose--response curve was discernable]. This assumption of linearity at the relevant part of the dose--response curve is necessary to extrapolate equivalent risk levels from U.S. EPA reference values derived from BMD modeling, and it is consistent with methods proposed in the U.S. EPA draft cancer risk assessment guidelines (U.S. EPA 1999d). Such risk-level extrapolation is not possible using the NOAEL/LOAEL approach.

[FIGURE 1 OMITTED]

Methods for risk-level estimation varied between reference values based on quantal end points and those based on continuous end points. For BMD/BMC values derived from quantal critical effect data, we estimated risk from exposure at concentrations equal to established RfD and RfC values by extrapolating linearly from the point represented by the BMR at the BMDL/BMCL to the established RfD and RfC values (Figure 1). We divided the risk at the BMR by the composite UF for those BMD models that were linear or supra-linear. For example, to estimate risk from exposure to chloroform's RfC, we divided the estimated risk level at the point of departure (1 in 10 for BMR = 10%) by the composite UF of 100, to arrive at a risk of 1 in 1,000. For BMD/BMC values derived from continuous critical effect data (normally distributed), a change in response of 1 standard deviation from control is considered roughly equivalent to a 10% increase in risk of adverse response from exposure (e.g., benzene's BMR = change of 1 standard deviation in lymphocyte count compared with control mean) (U.S. EPA 2000a, 2003). Therefore, when data quality and distribution allowed, we treated the dose that resulted in a 1-standard-deviation change from control as equivalent to BM[D.sub.10]/BM[C.sub.10] (BMD that equals a BMR of 10%/BMC that equals a BMR of 10%) values derived from quantal data. For assessments based on sublinear dose--response curves, we estimated risk of exposure at the RfD/RfC dose levels by extrapolating the BMD model response function to the RfD/RfC (i.e., using the BMD model, we estimated risk by putting the exposure equal to the RfD/RfC in the model).

For all chemicals in our assessment group with adequate data, we calculated the ratio of the central estimate (BMD or BMC) to the lower statistical confidence limit on the benchmark dose (BMDL) or concentration (BMCL) (Tables 1 and 3). This ratio (e.g., BMD/BMDL) provides a metric to compare the relative impact on estimated risk levels resulting from the selection of the BMD/BMC versus the BMDL/BMCL as the point of departure. Finally, among the studies that identified NOAELs, we compared the modeled BMDL and BMCL values with the empirical NOAELs as a means to investigate how using BMDL/BMCL values versus NOAELs compares with previous RfD/RfC methods based on the NOAEL approach.

Results

We found that 13 out of 23 (57%) of the BMD and BMC values were derived from quantal versus continuous data. A 10% additional risk or 10% change from control mean response was selected as the BMR for 17 of the 23 assessments, and a 5% BMR was selected for 3 of the remaining 6 assessments (Tables 6 and 7) [National Toxicology Program (NTP) 1993; U.S. EPA 1995a, 1995b, 1995c, 1995d, 1997a, 1998a, 1998c, 1998e, 1998g, 1998i, 1999b, 2000c, 2601a, 200lb, 2001d, 2002a, 2002e]. The BMR v/dues for benzene's BMC and BMD and for phenol's BMD were based on a 1-standard-deviation change in acute lymphocyte count and maternal body weight, respectively, compared with the control mean (U.S. EPA 2002c, 2003).

Of the 21 BMD and BMC values for which sufficient dose--response information was available, we found that 16 (76%) were derived from dose--response data fitted to linear or supralinear models in the observed dose range (Table 5) (NRC 2000; NTP 1993, 1998; U.S. EPA 1995b, 1995d, 1997b, 1998b, 1998c, 1998d, 1998f, 1998h, 1998j, 1999c, 2000c, 2001c, 2001e, 2002b, 2002d, 2002e, 2003). Seven assessments were based on linear models (two linear models; three polynomial models with [[beta].sub.i] [congruent to] 0 for i > 1; two power models with k [congruent to] 1), nine were based on supralinear models, and five were based on sublinear models. Sufficient information was not available to determine the shape of the fitted model for two assessments, carbon disulfide and 1,1,1,2-tetrafluoroethane (i.e., the response function and model parameters were not provided) (U.S. EPA 1995a, 1995c).

We calculated 17 RfD and RfC equivalent risk levels (for 14 compounds) assuming linear dose-response curves. These risk estimates ranged from 1 in 10,000 to 5 in 1,000 for the oral route of exposure for compounds with RfDs based on BMD values, and from 1 in 10,000 to 3 in 1,000 for inhalation for compounds with RfCs based on BMC values (Tables 6 and 7). Figures 2 and 3 present the RfD and RfC equivalent risk estimates on a logarithmic scale for these chemicals with linear or supralinear dose--response curves at the BMD/BMC. For four RfD and RfC equivalent risk levels (for 3 compounds), we used the sublinear dose-response model to calculate risk at the RfD or RfC. These risk estimates ranged from 3 in 1,000,000,000 to 1 in 100,000 from the oral route of exposure for compounds with RfDs based on BMD values, and from 3 in 1,00.0,000 to 8 in 10,000 from inhalation for compounds with Rff]s based on BMC values (Tables 6 and 7).

[FIGURES 2-3 OMITTED]

Five of 21 reference values (24%) reviewed for this assessment corresponded to estimated risk levels greater than 1 in 1,000. Insufficient information was available to estimate risk from exposure at two reference values that were based on continuous response data, chromium VI particulates and naphthalene (i.e., the response function, underlying distribution of the end point, or mean response and standard deviation of the treatment group and controls were not provided). Figure 4 presents the distribution of estimated risk levels from human exposures at established RfD and RfC values for compounds with a linear or supralinear dose-response curve at the BMD. Risk estimates for four assessments derived from sublinear dose-response curves are presented in Tables 6 and 7.

[FIGURE 4 OMITTED]

Among the chemicals for which the RfD was based on a BMD, the BMD/BMDL ratio ranged from 1.3 to 3.0. Among the chemicals for which the RfC was based on a BMC, the BMC/BMCL ratio ranged from 1.1 to 2.3 (Tables 1 and 3). Thus, using the central estimate of the BMD or BMC (maximum likelihood estimate) instead of the lower statistical confidence limit (BMDL or BMCL) as the point of departure would result in a 1-to 3-fold difference in the estimated risk levels (Figures 2 and 3).

The effect level extrapolation factor (ELE) is an UF analogous to the LOAEL-to-NOAEL extrapolation factor. ELEs were applied in the assessments of three compounds, 1,3-butadiene (RfC), benzene (RfC and RfD), and ethylene glycol monobutyl ether (RFC) (Tables 2 and 4) (U.S. EPA 1999b, 2002e, 2003). Thus, no ELE factor was assigned for 16 of 17 assessments'that were based on a BMR of 10%.

When we compared the points of departure (i.e., BMDL/BMCL values) with the NOAELs, we found that the points of departure were higher than the NOAELs in 10 of the 14 studies with identified NOAELs (Figure 5). The BMDL values were up to 4.6 times higher than the empirical NOAELs (range, 0.5-4.6), and the BMCL values were up to 3.9 times higher than the empirical NOAELs (range, 0.2-3.9) (Tables 1 and 3).

[FIGURE 5 OMITTED]

Discussion

To determine whether U.S. EPA reference values represent negligibly small risk levels, we reviewed and synthesized currently available risk assessment information on chemicals for which established RfD and RfC values are based on BMD modeling. For RfDs and RfCs derived from linear or supralinear dose-response curves, our risk estimates ranged from 1 in 10,000 to 5 in 1,000 for the oral route of exposure, and from 1 in 10,000 to 3 in 1,000 for inhalation. Risk estimates for RfDs and RfCs derived from sublinear dose--response curves ranged from 3 in 1,000,000,000 to 8 in 10,000. Twenty-four percent of reference values reviewed for this assessment corresponded to estimated risk levels greater than 1 in 1,000. The estimated risk of exposure to 1,1-dichloroethylene at its RfC, for example, corresponded to a 3-in-l,000 risk of adverse effect [liver toxicity (fatty change)].

The BMD methodology is the first step in the development of continuous risk functions that can be used to estimate risks at different exposures rather than using an RfD/RfC approach, which has limited use in the decision-making process. For example, BMD and BMC values that are based on the same level of adverse response (e.g., BMR = 10%) can be used to rank the potential hazard of exposure to multiple toxicants. Further application of BMD models, such as has been done here, can be used for estimating adverse noncancer health outcomes from different exposures for other risk-ranking exercises, regulatory policy development, and cost/benefit analyses.

The U.S. EPA used a variety of fitted models to calculate the BMD/BMC values found in IRIS (e.g., K power, linear, quantal-linear, exponential polynomial, and Weibull). To compare RfD and RfC equivalent risk levels, we assumed that the dose-response curves for the chemicals in our assessment group are linear at doses below the point of departure. This assumption could have resulted in both underestimates and overestimates of risk. In the case of a supralinear dose-response curve at low doses, for example, this assumption may have resulted in an underestimate of risk. Among the chemicals we reviewed, 9 of the 21 assessments with sufficient information to determine the shape of the dose-response curve were based on supralinear functions. In the case of a sublinear dose-response, this assumption may have resulted in a marked overestimate of risk. For the 5 assessments based on sublinear dose-response curves, therefore, we did not assume linearity for low dose extrapolation and risk estimation.

We believe that the assumption of linearity in the relevant part of the dose-response curve is justified and useful to compare risk levels among this group of compounds. Seventy-six percent of BMD and BMC values considered in this assessment were derived from dose--response data fitted to linear or supralinear models. Furthermore, the range of extrapolation for the RfD/RfC calculations was not large among this group, with most based on points of departure extrapolated to 2 orders of magnitude or less (7 were extrapolated to 1 order of magnitude, 13 were extrapolated to 2 orders of magnitude, and 3 were extrapolated to 3 orders of magnitude). The average and median composite UFs among the compounds in our assessment are 340 and 100, respectively. This implies that even if the dose--response

curve for a particular compound is not strictly linear at much lower doses, we could expect the potential impact on the risk estimate to be relatively small.

Current U.S. EPA methodology for reference value derivation assumes that the established RfDs/RfCs represent negligibly small risk levels. For assessments that have linear dose--response curves, the extrapolation from the point of departure is typically 2 orders of magnitude or less. Therefore, for the RfD/RfC values to represent risk levels that are below regulatory concern, the dose--response curve would have to drop off sharply after the point of departure. This assumption seems unlikely, especially given our finding that a large number of the assessments we reviewed (9 of 21) were based on supralinear dose--response functions. Although this supralinearity may carry significant implications for risk assessment, more research is needed to determine whether these dose-response relationships remain supralinear at very low doses. On the other hand, assessments based on dose--response curves that are not monotonic may have sublinear or stepwise relationships below the observed data.

Using the BMDL or BMCL as the point of departure in the risk assessment of noncarcinogenic compounds rather than the BMD or BMC central estimate is generally characterized as a conservative assumption (in the health-protective sense). We found that using the central estimate of the BMD (maximum likelihood estimate) instead of the lower bound estimate as the point of departure results in a 1-to 3-fold difference in the risk estimates. According to the U.S. EPA draft BMD guidelines (U.S. EPA 2000a), a lower confidence limit is placed on the BMD to obtain a dose (BMDL) that assures with high confidence (e.g., 95%) that the BMR is not exceeded. This process of using the BMDL rewards better experimental design and procedures that provide more precise estimates of the BMD, resulting in tighter confidence intervals and thus BMDLs that are closer to the central estimate. Our results suggest that the current practice of using the statistical lower bound estimate versus the maximum likelihood estimate as the point of departure is reasonable and does not substantially bias the risk estimate.

For carcinogens, the U.S. EPA typically develops a linear estimate of the slope of the dose--response curve, under the assumption that the curve is linear at low doses. This allows for quantification of risk at any given level of exposure. The U.S. EPA has defined 1 in 1,000,000 excess cancer risk as a de minimis risk level for cancer (CaldweU et al. 1998; Clean Air Act Amendments 1990; Fiori and Meyerhoff 2002; U.S. EPA 1991), although regulatory actions are sometimes limited to instances where risk exceeds 1 in 100,000. Among compounds in IRIS with RfDs and RfCs based on BMD modeling, however, we found risk estimates as great as 5 in 1,000. Although noncancer outcomes may in some instances be reversible and considered less severe, this finding calls into question the assumption that noncancer RfD and RfC values represent "acceptable levels" of exposure. In addition, some of the noncancer health end points considered in this assessment are severe and irreversible events, for example, ovarian atrophy (1,3-butadiene) and developmental neuropsychologic impairment (methylmercury), highlighting the need for a renewed discussion within the public health community about what should be considered an "acceptable level" of risk from exposure to toxicants with noncancer health end points.

Most of the BMDLs and BMCLs used as points of departure in IRIS are based on 10% BMRs, many with values higher than the empirically derived NOAELs. This research should help inform discussions about whether this level of BMR is adequately protective of the public health, and whether human exposures at concentrations equal to the resulting reference values do in fact represent negligibly small risk levels.

Table 1. Risk assessment information for chemicals with oral RfDs
derived from benchmark modeling. (a)

                                NOAEL                     LOAEL
Chemical                     (mg/kg/day)               (mg/kg/day)

Quantal end point
  Beryllium and
    compounds (U.S.
    EPA 1998a)                   0.1                       --
  Chloroform (c)
    (U.S. EPA
    2001b)                       --                15 ([12.9.sub.ADJ])
  1,1-Dichloro-
    ethylene (U.S.
    EPA 2002a)                    9                        14
  1,3-Dichloro-
    propene (U.S.
    EPA 2000c)                   2.5                       --
  Hexachloro-
    cyclopentadiene
    (U.S. EPA
    2001d)                       --                 10 ([7.sub.ADJ])
Continuous end point
  Benzene (d) (U.S.
    EPA 2003)                    --                        1.2
  EGBE (e) (U.S.
    EPA 1999b)                   --                        59
  Methylmercury
    (U.S. EPA 2001a)             --                        --
  Naphthalene (f)
    (U.S. EPA 1998i)   100 ([71.sub.ADJ]) (b)      200 ([143.sub.ADJ])
  Phenol (g) (U.S.
    EPA 2002c)                   60                        --
  Tributyltin oxide
    (U.S. EPA 1997a)            0.025                      --

                            BM[D.sub.10]              BMD[L.sub.10]
Chemical                     (mg/kg/day)               (mg/kg/day)

Quantal end point
  Beryllium and
    compounds (U.S.
    EPA 1998a)                   1.4                      0.46b (b)
  Chloroform (c)
    (U.S. EPA
    2001b)               1.7 ([1.5.sub.ADJ])    1.2 ([1.0.sub.ADJ]) (b)
  1,1-Dichloro-
    ethylene (U.S.
    EPA 2002a)                   6.6                      4.6 (b)
  1,3-Dichloro-
    propene (U.S.
    EPA 2000c)                   5.1                      3.4 (b)
  Hexachloro-
    cyclopentadiene
    (U.S. EPA
    2001d)                       11                       6 (5)
Continuous end point
  Benzene (d) (U.S.
    EPA 2003)                    2.2                      1.2 (b)
  EGBE (e) (U.S.
    EPA 1999b)                   --                        --
  Methylmercury
    (U.S. EPA 2001a)             --                        --
  Naphthalene (f)
    (U.S. EPA 1998i)     171([122.sub.ADJ])        130 ([93.sub.ADJ])
  Phenol (g) (U.S.
    EPA 2002c)                   157                       93 (b)
  Tributyltin oxide
    (U.S. EPA 1997a)            0.05                     0.034 (b)

                            BM[D.sub.05]              BMD[L.sub.05]
Chemical                     (mg/kg/day)               (mg/kg/day)

Quantal end point
  Beryllium and
    compounds (U.S.
    EPA 1998a)                   --                        --
  Chloroform (c)
    (U.S. EPA
    2001b)                       --                        --
  1,1-Dichloro-
    ethylene (U.S.
    EPA 2002a)                   --                        --
  1,3-Dichloro-
    propene (U.S.
    EPA 2000c)                   --                        --
  Hexachloro-
    cyclopentadiene
    (U.S. EPA
    2001d)                       --                        --
Continuous end point
  Benzene (d) (U.S.
    EPA 2003)                    --                        --
  EGBE (e) (U.S.
    EPA 1999b)              [7.7.sub.HED]                5.1HED (b)
  Methylmercury
    (U.S. EPA 2001a)     1.4-2.6[E.sup.-03]      0.9-1.5[E.sup.-03] (b)
  Naphthalene (f)
    (U.S. EPA 1998i)             --                        --
  Phenol (g) (U.S.
    EPA 2002c)                   --                        --
  Tributyltin oxide
    (U.S. EPA 1997a)             --                        --

                                              RfD
Chemical               BMD/BMDL    UF     (mg/kg/day)

Quantal end point
  Beryllium and
    compounds (U.S.
    EPA 1998a)           3.0        300     0.002
  Chloroform (c)
    (U.S. EPA
    2001b)               1.4        100     0.01
  1,1-Dichloro-
    ethylene (U.S.
    EPA 2002a)           1.4        100     0.05
  1,3-Dichloro-
    propene (U.S.
    EPA 2000c)           1.5        100     0.03
  Hexachloro-
    cyclopentadiene
    (U.S. EPA
    2001d)               1.8      1,000     0.006
Continuous end point
  Benzene (d) (U.S.
    EPA 2003)            1.8        300     0.004
  EGBE (e) (U.S.
    EPA 1999b)           1.5         10     0.5
  Methylmercury
    (U.S. EPA 2001a)     1.6         10     0.0001
  Naphthalene (f)
    (U.S. EPA 1998i)     1.3      3,000     0.02
  Phenol (g) (U.S.
    EPA 2002c)           1.7        300     0.3
  Tributyltin oxide
    (U.S. EPA 1997a)     1.5        100     0.0003

Abbreviations: ADJ, adjusted for duration of exposure; BM[D.sub.10],
BMD that equals a BMR of 10%; BMD[L.sub.10], lower confidence limit on
the BM[D.sub.10]; BM[D.sub.05], BMD that equals a BMR of 5%;
BMD[L.sub.05], lower confidence limit on BM[D.sub.05]; [C.sub.max],
peak blood concentration; EGBE, ethylene glycol monobutyl ether; HED,
human dose of an agent that is believed to induce the same magnitude
of toxic effect as the experimental animal species concentration or
dose (this adjustment may incorporate toxicokinetic information on
the particular agent, if available, or use a default procedure, such
as assuming that daily oral doses experienced for a lifetime are
proportional to body weight raised to the 0.75 power).

(a) The reported number of significant figures is not standardized in
IRIS. (b) Point of departure. (c) RfD derived from the LOAEL (1,000-
fold UF) = 0.01 mg/kg/day; BMD-based RfD (100-fold UF) = 0.01
mg/kg/day. (d) Oral BMD[L.sub.[ADJ]] was derived from the
BMC[L.sub.[ADJ]] (8.2 mg/[m.sup.3]) by route-to-route extrapolation
with the assumptions that inhalation absorption was 50% and oral
absorption was 100% in the dose range near the BMC; BMDL (adjusted
for continuous exposure) = (8.2 mg/[m.sup.3] x 20 [m.sup.3]/day x
0.5)/70 kg = 1.2 mg/kg/day; former RfD derived from the LOAEL
(1,000-fold UF) = 0.001. (e) HED was calculated as follows: using
[C.sub.max] for 2-butoxyacetic acid as the dose metric, the
BMD[L.sub.05] was determined to be 64 [micro]M; physiologically based
pharmacokinetic modeling was used to "back-calculate" a human
equivalent dose of 5.1 mg/kg/day, assuming that rats and humans
receive their entire dose of EGBE from drinking water over a 12-hr
period each day. (f) RfDs were based on the NOAEL and BM[D.sub.10]
values adjusted for duration (e.g., BMD x 5/7 days); the RfD in IRIS
is derived from the NOAEL (3,000-fold UF) = 0.02 mg/kg/day;
prospective RfD derived from BMD (3,000-fold UF) = 0.03 mg/kg/day.
(g) BMD was based on a benchmark response of a 1-standard-deviation
change from the control mean.

Table 2. End points and UFs for chemicals with oral RfDs derived from
benchmark modeling.

                                             End point: quantal or
Chemical                      Reference      continuous

Beryllium and compounds     U.S. EPA 1998a   Quantal (small intestinal
                                               lesions)
Chloroform                  U.S. EPA 2001b   Quantal (fatty cyst
                                               formation in liver and
                                               elevated serum
                                               glutamate-pyruvate
                                               transaminase)
1,1-Dichloroethylene        U.S. EPA 2002a   Quantal [liver toxicity
                                               (fatty change)]
1,3-Dichloropropene         U.S. EPA 2000c   Quantal (chronic
                                               irritation of stomach)
Hexachlorocyclopentadiene   U.S. EPA 2001d   Quantal (chronic
                                               irritation of stomach)
Benzene                     U.S. EPA 2003    Continuous (decreased
                                               lymphocyte count)
EGBE                        U.S. EPA 1999b   Continuous (changes in
                                               mean corpuscular
                                               volume)
Methylmercury               U.S. EPA 2001a   Continuous (developmental
                                               neuropsychologic
                                               impairment)
Naphthalene                 U.S. EPA 1998i   Continuous (decreased
                                               mean terminal body
                                               weight in males)
Phenol                      U.S. EPA 2002c   Continuous (decreased
                                               maternal body weight
                                               gain)
Tributyltin oxide           U.S. EPA 1997a   Continuous (immunosup-
                                               pression; decrease in
                                               IgE titer)

                                                UF (a)
                           Composite
Chemical                      UF       Interspecies   Intraspecies

Beryllium and compounds        300          10             10
Chloroform                     100          10             10
1,1-Dichloroethylene           100          10             10
1,3-Dichloropropene            100          10             10
Hexachlorocyclopentadiene    1,000          10             10
Benzene                        300          --             10
EGBE                            10          --             10
Methylmercury                   10          --             10
Naphthalene                  3,000          10             10
Phenol                         300          10             10
Tributyltin oxide              100          10             10

                                     UF (a)

Chemical                   Subchronic   Database   ELE

Beryllium and compounds        --         3        --
Chloroform                     --          --      --
1,1-Dichloroethylene           --          --      --
1,3-Dichloropropene            --          --      --
Hexachlorocyclopentadiene     3 (b)       3 (b)    --
Benzene                       3           3         3
EGBE                           --          --      --
Methylmercury                  --          --
Naphthalene                  10           3        --
Phenol                         --         3        --
Tributyltin oxide              --          --      --

Abbreviations: EGBE, ethylene glycol monobutyl ether; ELE, effect
level extrapolation factor.

(a) Interspecies extrapolation, intraspecies differences (human
variability), subchronic-to-chronic extrapolation, database
deficiencies, and ELE. (b) UFs assigned a value of 10 1/2 were rounded
to 3.

Table 3. Risk assessment information for chemicals with RfCs
derived from benchmark modeling. (a)

Chemical                               NOAEL

Quantal end point
  Antimony trioxide (b)           0.51 ([0.42.sub.HEC])
    (U.S. EPA 1995b)
  1,3-Butadiene (U.S.                       --
    EPA 2002e)
  1,1-Dichloroethylene            99.2 ([17.7.sub.HEC])
    (U.S. EPA 2002a)
  1,3-Dichloropropene                 [3.7.sub.ADJ]
    (U.S. EPA 2000c)
  Methyl methacrylate             102.4 ([18.2.sub.ADJ])
    (U.S. EPA 1998e)
  Methylene diphenyl              0.2 ([0.036.sub.ADJ])
    diisocyanate
    (U.S. EPA 1998g)
  Phosphoric acid                   50 ([2.7.sub.ADJ])
    (U.S. EPA 1995d)
  1,1,1,2-Tetrafluoroethane          [7,450.sub.HEC]
    (U.S. EPA 1995a)
Continuous end point
  Benzene (d) (U.S.                         --
    EPA 2003)
  Carbon disulfide (e)             15.9 ([5.7.sub.ADJ])
    (U.S. EPA 1995c)
  Chromium VI (particulates)                --
    (U.S. EPA 1998c)
  EGBE (U.S. EPA                            --
    1999b)

Chemical                                  LOAEL

Quantal end point
  Antimony trioxide (b)                     --
    (U.S. EPA 1995b)
  1,3-Butadiene (U.S.                      2.5
    EPA 2002e)
  1,1-Dichloroethylene            297.8 ([53.2.sub.HEC])
    (U.S. EPA 2002a)
  1,3-Dichloropropene                 [14.9.sub.ADJ]
    (U.S. EPA 2000c)
  Methyl methacrylate                       --
    (U.S. EPA 1998e)
  Methylene diphenyl               1.0 ([0.18.sub.ADJ])
    diisocyanate
    (U.S. EPA 1998g)
  Phosphoric acid                          180
    (U.S. EPA 1995d)
  1,1,1,2-Tetrafluoroethane          [37,250.sub.HEC]
    (U.S. EPA 1995a)
Continuous end point
  Benzene (d) (U.S.                   [8.7.sub.ADJ]
    EPA 2003)
  Carbon disulfide (e)            39.2 ([14.0.sub.ADJ])
    (U.S. EPA 1995c)
  Chromium VI (particulates)               0.05
    (U.S. EPA 1998c)
  EGBE (U.S. EPA                      [150.sub.HEC]
    1999b)

Chemical                            BM[C.sub.10]         BMC[L.sub.10]

Quantal end point
  Antimony trioxide (b)                 1.43                 0.87
    (U.S. EPA 1995b)
  1,3-Butadiene (U.S.                   2.25                 1.98 (c)
    EPA 2002e)
  1,1-Dichloroethylene                 59.95                 38.9
    (U.S. EPA 2002a)
  1,3-Dichloropropene              [5.91.sub.ADJ]              --
    (U.S. EPA 2000c)
  Methyl methacrylate                 178.7                   143
    (U.S. EPA 1998e)
  Methylene diphenyl               [0.22.sub.ADJ]              --
    diisocyanate
    (U.S. EPA 1998g)
  Phosphoric acid                       150                   100
    (U.S. EPA 1995d)
  1,1,1,2-Tetrafluoroethane              --                  46,000
    (U.S. EPA 1995a)
Continuous end point
  Benzene (d) (U.S.                    43.77                   23
    EPA 2003)
  Carbon disulfide (e)                   --                   55.1
    (U.S. EPA 1995c)
  Chromium VI (particulates)           0.036                 0.016
    (U.S. EPA 1998c)
  EGBE (U.S. EPA                         --                     --
    1999b)

Chemical                        BMC[L.sub.10[ADJ]]   BMC[L.sub.10[HEC]]

Quantal end point
  Antimony trioxide (b)                 0.16                 0.074 (c)
    (U.S. EPA 1995b)
  1,3-Butadiene (U.S.                    --                     --
    EPA 2002e)
  1,1-Dichloroethylene                   --                  6.9 (c)
    (U.S. EPA 2002a)
  1,3-Dichloropropene                   3.66                 0.72 (c)
    (U.S. EPA 2000c)
  Methyl methacrylate                  25.6                  7.2 (c)
    (U.S. EPA 1998e)
  Methylene diphenyl                    0.14                 0.06 (c)
    diisocyanate
    (U.S. EPA 1998g)
  Phosphoric acid                       5.4                  3.4 (c)
    (U.S. EPA 1995d)
  1,1,1,2-Tetrafluoroethane            8,200                8,200 (c)
    (U.S. EPA 1995a)
Continuous end point
  Benzene (d) (U.S.                    8.2 (c)                  --
    EPA 2003)
  Carbon disulfide (e)                19.7 (c)                  --
    (U.S. EPA 1995c)
  Chromium VI (particulates)         0.034 (c)                  --
    (U.S. EPA 1998c)
  EGBE (U.S. EPA                         --                     --
    1999b)

Chemical                            BM[C.sub.05]         BMC[L.sub.05]

Quantal end point
  Antimony trioxide (b)                  --                     --
    (U.S. EPA 1995b)
  1,3-Butadiene (U.S.                    --                     --
    EPA 2002e)
  1,1-Dichloroethylene                   --                     --
    (U.S. EPA 2002a)
  1,3-Dichloropropene                    --                     --
    (U.S. EPA 2000c)
  Methyl methacrylate                    --                   104.6
    (U.S. EPA 1998e)
  Methylene diphenyl                     --                     --
    diisocyanate
    (U.S. EPA 1998g)
  Phosphoric acid                       112                    64
    (U.S. EPA 1995d)
  1,1,1,2-Tetrafluoroethane              --                     --
    (U.S. EPA 1995a)
Continuous end point
  Benzene (d) (U.S.                      --                     --
    EPA 2003)
  Carbon disulfide (e)
    (U.S. EPA 1995c)
  Chromium VI (particulates)             --                     --
    (U.S. EPA 1998c)
  EGBE (U.S. EPA                   [530.sub.HEC]      [380.sub.HEC] (c)
    1999b)

                                 BMC/
Chemical                         BMCL      UF         RfC

Quantal end point
  Antimony trioxide (b)          1.6        300      0.0002
    (U.S. EPA 1995b)
  1,3-Butadiene (U.S.            1.1      1,000      0.002
    EPA 2002e)
  1,1-Dichloroethylene           1.5         30      0.2
    (U.S. EPA 2002a)
  1,3-Dichloropropene            1.6         30      0.02
    (U.S. EPA 2000c)
  Methyl methacrylate            1.2         10      0.7
    (U.S. EPA 1998e)
  Methylene diphenyl             1.6        100      0.0006
    diisocyanate
    (U.S. EPA 1998g)
  Phosphoric acid                1.5        300      0.01
    (U.S. EPA 1995d)
  1,1,1,2-Tetrafluoroethane       --        100     80
    (U.S. EPA 1995a)
Continuous end point
  Benzene (d) (U.S.              1.9        300      0.03
    EPA 2003)
  Carbon disulfide (e)                       30      0.7
    (U.S. EPA 1995c)
  Chromium VI (particulates)     2.3        300      0.0001
    (U.S. EPA 1998c)
  EGBE (U.S. EPA                 1.4         30     13
    1999b)

Abbreviations: ADJ, dose that has been adjusted for duration of
exposure; BM[C.sub.10], BMC that equals a BMR of 10%; BMC[L.sub.10],
lower confidence limit on the BM[C.sub.10]; BM[C.sub.05], BMC that
equals a BMR of 5%; BMC[L.sub.05], lower confidence limit on
BM[C.sub.05]; HEC, human equivalent concentration [the human
concentration (for inhalation exposure) of an agent that is believed
to induce the same magnitude of toxic effect as the experimental
animal species concentration or dose; this adjustment may incorporate
toxicokinetic information on the particular agent, if available, or
use a default procedure, such as assuming that daily oral doses
experienced for a lifetime are proportional to body weight raised to
the 0.75 power]; MVh, human ambient default minute volume; MVho,
human occupational default minute volume; RDDR, regional deposited
dose ratio (the ratio of the regional deposited dose calculated for a
give exposure in the animal species of interest to the regional
deposited dose of the same exposure in a human; this ratio is used to
adjust the exposure effect level for interspecies dosimetric
differences to derive a human equivalent concentration for particles).

(a) The reported number of significant figures is not standardized in
IRIS. (b) Point of departure is the BMC[L.sub.10[HEC]] (BMC[L.sub.
10[HEC]] = BMC[L.sub.10[ADJ]] x RDDR = 0.074 mg/[m.sup.3]. (c) Point
of departure, (d) BMC was based on a benchmark response of a
1-standard-deviation change from the control mean; the BMCL is the
statistical lower bound estimate on the dose corresponding to a
1-standard-deviation change from control. (e) BMC is based on an 8-hr
time-weighted average occupational exposure; its point of departure is
BMC[L.sub.10[HEC]] = 55.1 mg/[m.sup.3] x (MVho/MVh x 5/7 days) = 19.7
mg/[m.sup.3]. MVho = 10 [m.sup.3]/day; MVh = 20 [m.sup.3]/day.

Table 4. End points and UFs for chemicals with RfCs derived from
benchmark modeling.

                                                   End point: quantal
Chemical                          Reference        or continuous

Antimony trioxide                 U.S. EPA 1995b   Quantal (pulmonary
                                                     toxicity, chronic
                                                     interstitial
                                                     inflammation)
1,3-Butadiene                     U.S. EPA 2002e   Quantal (ovarian
                                                     atrophy)
1,1-Dichloroethylene              U.S. EPA 2002a   Quantal [liver
                                                     toxicity (fatty
                                                     change)]
1,3-Dichloropropene               U.S. EPA 2000c   Quantal (hyperplasia
                                                     of nasal
                                                     epithelium)
Methyl methacrylate               U.S. EPA 1998e   Quantal (degenera-
                                                     tion/atrophy of
                                                     olfactory
                                                     epithelium)
Methylene diphenyl diisocyanate   U.S. EPA 1998g   Quantal (hyperplasia
                                                     of the olfactory
                                                     epithelium)
Phosphoric acid                   U.S. EPA 1995d   Quantal (bronchiolar
                                                     fibrosis)
1,1,1,2-Tetrafluoroethane         U.S. EPA 1995a   Quantal (Leydig cell
                                                     hyperplasia)
Benzene                           U.S. EPA 2003    Continuous
                                                     (decreased
                                                     lymphocyte count)
Carbon disulfide                  U.S. EPA 1995c   Continuous
                                                     (peripheral
                                                     nervous system
                                                     dysfunction)
Chromium VI (particulates)        U.S. EPA 1998c   Continuous (lactate
                                                     dehydrogenase in
                                                     bronchioalveolar
                                                     lavage fluid)
EGBE                              U.S. EPA 1999b   Continuous (changes
                                                     in red blood cell
                                                     count)

                                                   UF (a)

                                  Composite   Inter-     Intra-
Chemical                             UF       species   aspecies

Antimony trioxide                     300        3         10

1,3-Butadiene                       1,000        3         10
1,1-Dichloroethylene                   30        3         10
1,3-Dichloropropene                    30        3         10
Methyl methacrylate                    10        3          3
Methylene diphenyl diisocyanate       100        3         10
Phosphoric acid                       300        3         10
1,1,1,2-Tetrafluoroethane             100        3         10
Benzene                               300       --         10
Carbon disulfide                       30       --          3
Chromium VI (particulates)            300        3         10
EGBE                                   30       --         10

                                               UF (a)

Chemical                          Subchronic   Database   ELE

Antimony trioxide                     3           3       --

1,3-Butadiene                         --          3       10
1,1-Dichloroethylene                  --          --      --
1,3-Dichloropropene                   --          --      --
Methyl methacrylate                   --          --      --

Methylene diphenyl diisocyanate       --          3       --
Phosphoric acid                       10          --      --
1,1,1,2-Tetrafluoroethane             --          3       --
Benzene                               3           3        3
Carbon disulfide                      --          10      --

Chromium VI (particulates)            10          --      --

EGBE                                  --          --       3

Abbreviations: EGBE, ethylene glycol monobutyl ether; ELE, effect
level extrapolation factor.

(a) Interspecies extrapolation, intraspecies differences (human
variability), subchronic-to-chronic extrapolation, database
deficiencies, and ELE.

Table 5. Fitted BMD models and dose-response curve characterizations
for 23 RfD/RfC assessments.

Chemical                             Reference value   End point

Antimony trioxide (U.S. EPA 1995b)         RfC          Quantal
EGBE (U.S. EPA 1999b, 1999c; NTP
  1993, 1998)                              RfC         Continuous
Methylene diphenyl diisocyanate
  (U.S. EPA 1998g, 1998h)                  RfC          Quantal
Methylmercury (U.S. EPA 2001a; NRC
  2000)                                    RfD         Continuous
Phenol (U.S. EPA 2002c, 2002d)             RfD         Continuous
Phosphoric acid (U.S. EPA 1995d)           RfC          Quantal
Tributyltin oxide (U.S. EPA 1997a,
  1997b)                                   RfD         Continuous
Benzene (U.S. EPA 2003)                    RfD         Continuous
Benzene                                    RfC         Continuous
Beryllium (U.S. EPA 1998a, 1998b)          RfD          Quantal
1,3-Butadiene (U.S. EPA 2002e)             RfC          Quantal
Chloroform (U.S. EPA 2001b, 2001c)         RfD          Quantal
1,1-Dichloroethylene (U.S. EPA
  2002a, 2002b)                            RfD          Quantal
1,1-Dichloroethylene                       RfC          Quantal
EGBE (U.S. EPA 1999b, 1999c; NTP
  1993, 1998)                              RfD         Continuous
Naphthalene (U.S. EPA 1998i,
  1998j)                                   RfD         Continuous
Chromium VI (particulates) (U.S.
  EPA 1998c, 1998d)                        RfC         Continuous
1,3-Dichloropropene (U.S. EPA
  2000c, 2000d)                            RfD          Quantal
1,3-Dichloropropene                        RfC          Quantal
Hexachlorocyclopentadiene (U.S.
  EPA 2001d, 2001e)                        RfD          Quantal
Methyl methacrylate (U.S. EPA
  1998e, 1998f)                            RfC          Quantal
Carbon disulfide (U.S. EPA 1995c)          RfC         Continuous
1,1,1,2-Tetrafluoroethane (U.S.
  EPA 1995a)                               RfC          Quantal

Chemical                             Fitted models (a)

Antimony trioxide (U.S. EPA 1995b)   Linear and Weibull (b)
EGBE (U.S. EPA 1999b, 1999c; NTP
  1993, 1998)                        Power model (k = 0.95)
Methylene diphenyl diisocyanate
  (U.S. EPA 1998g, 1998h)            Polynomial regression
                                       ([[beta].sub.i] = 0) (c)
Methylmercury (U.S. EPA 2001a; NRC
  2000)                              Power model (k= 1) (d)
Phenol (U.S. EPA 2002c, 2002d)       Polynomial ([[beta].sub.2]
                                       [congruent to] 0) (e)
Phosphoric acid (U.S. EPA 1995d)     Linear and Weibull (b)
Tributyltin oxide (U.S. EPA 1997a,
  1997b)                             Polynomial mean response
                                       ([[beta].sub.i]= 0) (c)
Benzene (U.S. EPA 2003)              Log-linear
Benzene                              Log-linear
Beryllium (U.S. EPA 1998a, 1998b)    Exponential polynomial
1,3-Butadiene (U.S. EPA 2002e)       Weibull
Chloroform (U.S. EPA 2001b, 2001c)   Quantal-linear
1,1-Dichloroethylene (U.S. EPA
  2002a, 2002b)                      Gamma
1,1-Dichloroethylene                 Quantal-linear
EGBE (U.S. EPA 1999b, 1999c; NTP
  1993, 1998)                        Power model (k = 0.66)
Naphthalene (U.S. EPA 1998i,
  1998j)                             Polynomial and power
Chromium VI (particulates) (U.S.
  EPA 1998c, 1998d)                  Polynomial mean response
1,3-Dichloropropene (U.S. EPA
  2000c, 2000d)                      Gamma
1,3-Dichloropropene                  Gamma
Hexachlorocyclopentadiene (U.S.
  EPA 2001d, 2001e)                  Log-logistic
Methyl methacrylate (U.S. EPA
  1998e, 1998f)                      Polynomial mean response
Carbon disulfide (U.S. EPA 1995c)    Weibull and polynomial
1,1,1,2-Tetrafluoroethane (U.S.
  EPA 1995a)                         Weibull and polynomial
                                       (multistage)

                                          Shape of
Chemical                             dose-response curve

Antimony trioxide (U.S. EPA 1995b)         Linear
EGBE (U.S. EPA 1999b, 1999c; NTP
  1993, 1998)                              Linear
Methylene diphenyl diisocyanate
  (U.S. EPA 1998g, 1998h)                  Linear
Methylmercury (U.S. EPA 2001a; NRC
  2000)                                    Linear
Phenol (U.S. EPA 2002c, 2002d)             Linear
Phosphoric acid (U.S. EPA 1995d)           Linear
Tributyltin oxide (U.S. EPA 1997a,
  1997b)                                   Linear
Benzene (U.S. EPA 2003)                  Supralinear
Benzene                                  Supralinear
Beryllium (U.S. EPA 1998a, 1998b)        Supralinear
1,3-Butadiene (U.S. EPA 2002e)           Supralinear
Chloroform (U.S. EPA 2001b, 2001c)       Supralinear
1,1-Dichloroethylene (U.S. EPA
  2002a, 2002b)                          Supralinear
1,1-Dichloroethylene                   Supralinear (f)
EGBE (U.S. EPA 1999b, 1999c; NTP
  1993, 1998)                            Supralinear
Naphthalene (U.S. EPA 1998i,
  1998j)                               Supralinear (g)
Chromium VI (particulates) (U.S.
  EPA 1998c, 1998d)                       Sublinear
1,3-Dichloropropene (U.S. EPA
  2000c, 2000d)                           Sublinear
1,3-Dichloropropene                       Sublinear
Hexachlorocyclopentadiene (U.S.
  EPA 2001d, 2001e)                       Sublinear
Methyl methacrylate (U.S. EPA
  1998e, 1998f)                           Sublinear
Carbon disulfide (U.S. EPA 1995c)          NA (h)
1,1,1,2-Tetrafluoroethane (U.S.
  EPA 1995a)                               NA (h)

Abbreviations: EGBE, ethylene glycol monobutyl ether; NA, not
available.

(a) Models were defined for an observed range of experimental data.
(b) BMCs were obtained using both Weibull and linear models; the
models gave similar goodness of fit to the data and BMC estimates. (c)
Linear dose-response curve because assessment is based on a polynomial
model with [[beta].sub.i] = 0 for i > 1. (d) Model restricted to not
allow supralinear forms. (e) Essentiaily linear dose-response curve
because squared coefficient term of second-degree polynomial model is
insignificantly small ([[beta].sub.2] [congruent to] 0). (f) Shape of
dose-response curve determined supralinear based on visual inspection;
because slope parameter is small, curve approaches linear at low doses.
(g) Shape of dose-response curve determined supralinear based on
visual inspection; BMD model response function was not available. (h)
Shape of dose-response curve information was not available; assumed
linear or supralinear.

Table 6. Estimated risk levels from exposure at the RfD.

                                             Point
                                               of
                                             depar-
                                              ture
                                             (mg/kg/
Chemical                                      day)    BMR      UF

Beryllium and compounds (U.S. EPA 1998a)      0.46     10%     300
Chloroform (U.S. EPA 2001b)                   1.2      10%     100
1,1-Dichloroethylene (U.S. EPA 2002a)         4.6      10%     100
1,3-Dichloropropene (U.S. EPA 2000c)          3.4      10%     100
Hexachlorocyclopentadiene (U.S. EPA 2001d)    6.0      10%   1,000
Benzene (b) (U.S. EPA 2003)                   1.2     1 SD     300
EGBE (U.S. EPA 1999b; NTP 1993)               5.1       5%      10
Methylmercury (c) (U.S. EPA 2001a)            0.0009    5%      10
Naphthalene (d) (U.S. EPA 1998i)             93        10%   3,000
Phenol (U.S. EPA 2002c)                      93       1 SD     300
Tributyltin oxide (U.S. EPA 1997a)            0.03     10%     100

                                              RfD
                                              (mg/
                                              kg/
Chemical                                      day)    Risk estimate

Beryllium and compounds (U.S. EPA 1998a)     0.002    1 in 10,000
Chloroform (U.S. EPA 2001b)                  0.01     1 in 1,000
1,1-Dichloroethylene (U.S. EPA 2002a)        0.05     1 in 1,000
1,3-Dichloropropene (U.S. EPA 2000c)         0.03     1 in 100,000 (a)
Hexachlorocyclopentadiene (U.S. EPA 2001d)   0.006    3 in 109 (a)
Benzene (b) (U.S. EPA 2003)                  0.004    3 in 10,000
EGBE (U.S. EPA 1999b; NTP 1993)              0.5      2 in 1,000
Methylmercury (c) (U.S. EPA 2001a)           0.0001   5 in 1,000
Naphthalene (d) (U.S. EPA 1998i)             0.03          --
Phenol (U.S. EPA 2002c)                      0.3      3 in 10,000
Tributyltin oxide (U.S. EPA 1997a)           0.0003   1 in 10,000

                                             End point: quantal or
Chemical                                     continuous

Beryllium and compounds (U.S. EPA 1998a)     Quantal (small intestinal
                                               lesions)
Chloroform (U.S. EPA 2001b)                  Quantal (fatty cyst
                                               formation in liver and
                                               elevated serum
                                               glutamate-pyruvate
                                               transaminase)
1,1-Dichloroethylene (U.S. EPA 2002a)        Quantal [liver toxicity
                                               (fatty change)]
1,3-Dichloropropene (U.S. EPA 2000c)         Quantal (chronic
                                               irritation of stomach)
Hexachlorocyclopentadiene (U.S. EPA 2001d)   Quantal (chronic
                                               irritation of stomach)
Benzene (b) (U.S. EPA 2003)                  Continuous (decreased
                                               lymphocyte count)
EGBE (U.S. EPA 1999b; NTP 1993)              Continuous (changes in
                                               mean corpuscular volume)
Methylmercury (c) (U.S. EPA 2001a)           Continuous (developmental
                                               neuropsychological
                                               impairment)
Naphthalene (d) (U.S. EPA 1998i)             Continuous (decreased
                                               mean terminal body
                                               weight)
Phenol (U.S. EPA 2002c)                      Continuous (decreased
                                               maternal body weight
                                               gain)
Tributyltin oxide (U.S. EPA 1997a)           Continuous (immunosup-
                                               pression--decrease in
                                               IgE titer)

EGBE, ethylene glycol monobutyl ether.

(a) Because IRIS assessment is based on sublinear dose-response
curve, linearity was not assumed for low dose extrapolation, and risk
estimate was derived from the BMD model response function. (b) BMR is
expressed in terms of the standard deviation (in the absence of a
clear definition for an adverse effect for this continuous end point, a
default BMR of 1-standard-deviation change from the control mean was
selected). This default definition of a BMR for continuous end points
corresponds to an excess risk of approximately 10% for the proportion
of individuals below the second percentile (or above the 98th
percentile) of the control distribution for normally distributed
effects. Benzene's oral BMD[L.sub.[ADJ]] was derived from the
BMC[L.sub.[ADJ]]) (8.2 mg/[m.sup.3]) by route-to-route extrapolation
with the assumptions that inhalation absorption was 50% and oral
absorption was 100% in the dose range near the BMC. CBMR represents a
5% increased risk of neuropsychologic impairment compared to
background. (d) Insufficient data available to estimate risk level
(i.e., the response function, underlying distribution of the end
point, or mean response and standard deviation of the treatment group
and controls were not provided). Naphthalene's RfD in IRIS derived
from the NOAEL (3,000-fold uncertainty factor) = 0.02 mg/kg/day;
Tthe prospective RfD derived from the BMD (3,000-fold uncertainty
factor) = 0.03 mg/kg/day.

Table 7. Estimated risk levels from exposure at the RfC.

                                            Point of
                                            departure
Chemical                                      (mg/       BMR     UF
                                            [m.sup.3])

Antimony trioxide (U.S. EPA 1995b)            0.074       10%     300
1,3-Butadiene (U.S. EPA 2002e)                 1.98       10%   1,000
1,1 -Dichloroethylene (U.S. EPA 2002a)         6.9        10%      30
1,3-Dichloropropene (U.S. EPA 2002c)           0.72       10%      30
Methyl methacrylate (U.S. EPA 1998e)           7.2        10%      10
Methylene diphenyl diisocyanate (U.S. EPA
  1998g)                                       0.06       10%     100
Phosphoric acid (U.S. EPA 1995d)               3.4        10%     300
1,1,1,2-Tetrafluoroethane (U.S. EPA 1995a)    8,200       10%     100
Benzene (b) (U.S. EPA 2003)                    8.2       1 SD     300
Carbon disulfide (c) (U.S. EPA 1995c)          19.7       10%      30
Chromium VI (particulates) (d) (U.S. EPA
  1998c)                                      0.034       10%     300
EGBE (U.S. EPA 1999b; NTP 1993)                380         5%      30

                                             RfC (mg/    Risk
Chemical                                     [m.sup.3])  estimate

Antimony trioxide (U.S. EPA 1995b)             0.0002    3 in 10,000
1,3-Butadiene (U.S. EPA 2002e)                 0.002     1 in 10,000
1,1 -Dichloroethylene (U.S. EPA 2002a)         0.2       3 in 1,000
1,3-Dichloropropene (U.S. EPA 2002c)           0.02      3 in
                                                         [10.sup.6]
                                                         (a)
Methyl methacrylate (U.S. EPA 1998e)           0.7       8 in
                                                         10,000 (a)
Methylene diphenyl diisocyanate (U.S. EPA
  1998g)                                       0.0006    1 in 1,000
Phosphoric acid (U.S. EPA 1995d)               0.01      3 in 10,000
1,1,1,2-Tetrafluoroethane (U.S. EPA 1995a)    80         1 in 1,000
Benzene (b) (U.S. EPA 2003)                    0.03      3 in 10,000
Carbon disulfide (c) (U.S. EPA 1995c)          0.7       3 in 1,000
Chromium VI (particulates) (d) (U.S. EPA
  1998c)                                       0.0001    --
EGBE (U.S. EPA 1999b; NTP 1993)               13         2 in 1,000

                                             End point: quantal or
Chemical                                     continuous

Antimony trioxide (U.S. EPA 1995b)           Quantal (pulmonary
                                               toxicity, chronic
                                               interstitial
                                               inflammation)
1,3-Butadiene (U.S. EPA 2002e)               Quantal (ovarian atrophy)
1,1 -Dichloroethylene (U.S. EPA 2002a)       Quantal [liver toxicity
                                               (fatty change)]
1,3-Dichloropropene (U.S. EPA 2002c)         Quantal (hyperplasia of
                                               nasal epithelium)
Methyl methacrylate (U.S. EPA 1998e)         Quantal (degeneration/
                                               atropy of olfactory
                                               irepithelium)
Methylene diphenyl diisocyanate (U.S. EPA
  1998g)                                     Quantal (hyperplasia of
                                               the olfactory
                                               epithelium)
Phosphoric acid (U.S. EPA 1995d)             Quantal (bronchiolar
                                               fibrosis)
1,1,1,2-Tetrafluoroethane (U.S. EPA 1995a)   Quantal (Leydig cell
                                               hyperplasia)
Benzene (b) (U.S. EPA 2003)                  Continuous (decreased
                                               lymphocyte count)
Carbon disulfide (c) (U.S. EPA 1995c)        Continuous (peripheral
                                               nervous system
                                               dysfunction)
Chromium VI (particulates) (d) (U.S. EPA
  1998c)                                     Continuous (lactate
                                               dehydrogenase in
                                               bronchioalveotar lavage
                                               fluid)
EGBE (U.S. EPA 1999b; NTP 1993)              Continuous (changes in
                                               red blood cell count)

EGBE, ethylene glycol monobutyl ether.

(a) Because IRIS assessment is based on sublinear dose-response
curve, linearity was not assumed for low dose extrapolation, and risk
estimate was derived from the BMC model response function. (b) BMC was
based on a BMR of 1-standard-deviation change from the control mean
(in the absence of a clear definition for an adverse effect for this
continuous end point, a default BMR of 1-standard-deviation change
from the control mean was selected). This default definition of a BMR
for continuous end points corresponds to an excess risk of
approximately 10% for the proportion of individuals below the second
percentile (or above the 98th percentile) of the control distribution
for normally distributed effects. (c) A 10% relative change was
selected as an appropriate BMR for the nerve conduction velocity
measurements because this level is about equal to a difference of 1
standard deviation from the control, and because a change of about
10% would likely raise concern in a clinical setting. (d) Insufficient
data available to estimate risk level (i.e., the response function,
underlying distribution of the end point, or mean response and
standard deviation of the treatment group and controls were not
provided).

REFERENCES

Barnes DG, Daston GP, Evans JS, Jarabek AM, Kavlock R J, Kimmel CA, et al. 1995. Benchmark dose workshop: criteria for use of a benchmark dose to estimate a reference dose. Regal Toxicol Pharmacol 21:296-306.

Caldwell J, Woodruff T, Morello-Frosch R, Axelrad D. 1998. Application of hazard identification information for pollutants modeled in EPA's Cumulative Exposure Project. Toxicol Ind Health 14(3):429-454.

Clean Air Act Amendments of 1990. 1990. Public Law 101-549.

Crump KS. 1984. A new method for determining allowable daily intakes. Fundam Appl Toxicol 4:854-871.

--. 1995. Calculation of benchmark doses from continuous data. Risk Anal 15(1):79-89.

Fiori JM, Meyerhoff RD. 2002. Extending the threshold of regulation concept: de minimis limits for carcinogens and mutagens. Regul Toxicol Pharmacol 35(2 pt 1):209-216.

Gaylor D, Ryan L, Krewski D, Zhu Y. 1998. Procedures for calculating benchmark doses for health risk assessment. Regul Toxicol Pharmacol 28(2):150-164.

Gaylor DW, Kodell RL. 2000. Percentiles of the product of uncertainty factors for establishing probabilistic reference doses, Risk Anal 20(2):245-250.

Leisenring W, Ryan L. 1992. Statistical properties of the NOAEL. Regul Toxicol Pharmacol 15(2):161-171.

National Research Council (NRC). 2000. Toxicological Effects of Methylmercury. Washington, DC:National Academy Press.

NTP. 1993. Toxicity Studies of Ethylene Glycol Ethers: 2-Methoxyethanol, 2-Ethoxyethanol, 2-Butoxyethanol (CAS Nos. 109-86-4, 110-80-5, 111-78-2) Administered in Drinking Water to F344/N Rats and B6C3[F.sub.i] Mice. TOX-26. Research Triangle Park, NC:National Toxicology Program.

--. 1998. Toxicology and Carcinogenesis Studies of 2-Butoxyethanol (CAS No. 111-76-2)in F344/N Rats and B6C3[F.sub.1] Mice (Inhalation Studies). Technical Report 484. Research Triangle Park, NC:National Toxicology Program. Available: http://ehp.niehs.nih.gov/ntp/members/tr484/ tr484full.pdf [accessed 16 June 2003].

U.S. EPA. 1991. Amendments to the water quality standards regulation; compliance with CWA Section 303(c) (2) (B); proposed rule. Fed Beg 56(223):58420-58437.

--. 1995a. Integrated Risk Information System (IRIS) Risk Information for 1,1,1,2-Tetrafluoroethane. Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 1995b. Integrated Risk Information System (IRIS) Risk Information for Antimony Trioxide. Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 1995c. Integrated Risk Information System (IRIS) Risk Information for Carbon Disulfide. Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 1995d. Integrated Risk Information System (IRIS) Risk Information for Phosphoric Acid. Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 1997a. Integrated Risk Information System (IRIS) Risk Information for Tributyltin Oxide. Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 1997b. Toxicological Review of Tributyltin Oxide (5635-9) in Support of Summary Information on the Integrated Risk Information System (IRIS). Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 1998a. Integrated Risk Information System (IRIS) Risk Information for Beryllium and Compounds. Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 1998b. Toxicological Review of Beryllium (7440-41-7) in Support of Summary Information on the Integrated Risk Information System (IRIS). Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--.1998c. Integrated Risk Information System (IRIS) Risk Information for Chromium (VI). Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 1998d. Toxicological Review of Hexavalent Chromium (18540-29-9) in Support of Summary Information on the Integrated Risk Information System (IRIS). Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 1998e. Integrated Risk Information System (IRIS) Risk Information for Methyl Methacrylate. Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 1998f. Toxicological Review of Methyl Methacrylate (80-62-8) in Support of Summary Information on the Integrated Risk Information System (IRIS). Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 1998g. Integrated Risk Information System (IRIS) Risk Information for Methylene Diphenyl Diisocyanate. Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 1998h. Toxicological Review of Methylene Diphenyl Diisocyanate (101-68-8 and 9016-87-9) in Support of Summary Information on the Integrated Risk Information System (IRIS). Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 1998i. Integrated Risk Information System (IRIS) Risk Information for Naphthalene. Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 1998j. Toxicological Review of Naphthalene (91-20-3) in Support of Summary Information on the Integrated Risk Information System (IRIS). Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 1999a. Integrated Risk Information Service (IRIS) Glossary of IRIS Terms. Available: http://www.epa.gov/ iris/gloss8.htm [accessed 15 July 2002].

--. 1999b. Integrated Risk Information System (IRIS) Risk Information for Ethylene Glycol Monobutyl Ether (EGBE). Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 1999c. Toxicological Review of Ethylene Glycol Monobutyl Ether (111-76-2) in Support of Summary Information on the Integrated Risk Information System (IRIS). Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 1999d. Guidelines for Carcinogen Risk Assessment. Review Draft. NCEA-F-0644. Washington, DC:U.S. Environmental Protection Agency, Risk Assessment Forum.

--. 2000a. Benchmark Dose Technical Guidance Document. External Review Draft. EPA/630/R-00/001. Washington, DC:U.S. Environmental Protection Agency.

--. 2000b. Integrated Risk information System (IRIS) Homepage. Available: http://www.epa.gov/iriswebp/iris/ [accessed 13 June 2003].

--. 2000c. Integrated Risk Information System (IRIS) Risk Information for 1,3-Dichloropropene. Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 2000d. Toxicological Review of 1,3-Dichtoropropene (542-75-6) in Support of Summary Information on the Integrated Risk Information System (IRIS). Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 2001a. Integrated Risk Information System (IRIS) Risk Information for Methylmercury (MeHg). Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 2001b. Integrated Risk Information System (IRIS) Risk Information for Chloroform. Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 2001c. Toxicological Review of Chloroform (67-86-3)in Support of Summary Information on the Integrated Risk Information System (IRIS). Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 2001d. Integrated Risk Information System (IRIS) Risk Information for Hexachlorocyclopentadiene. Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 2001e. Toxicological Review of Hexachlorocyclopentadiene (77-47-4) in Support of Summary Information on the Integrated Risk Information System (IRIS). Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 2002a. Integrated Risk Information System (IRIS) Risk Information for 1,1-Dichloroethylene. Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 2002b. Toxicological Review of 1,1-Dichloroethylene (75-35-4) in Support of Summary Information on the Integrated Risk Information System (IRIS). Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 2002c. Integrated Risk Information System (IRIS) Risk Information for Phenol. Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 2002d. Toxicological Review of Phenol (108-95-2) in Support of Summary Information on the Integrated Risk Information System (IRIS). Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 2002e. Integrated Risk Information System (IRIS) Risk Information for 1,3-Butadiene. Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

--. 2003. Integrated Risk Information System (IRIS) Risk Information for Benzene. Washington, DC:U.S. Environmental Protection Agency, National Center for Environmental Assessment.

Rosemary Castorina (1,2) and Tracey J. Woodruff (2)

(1) Center for Children's Environmental Health Research, School of Public Health, University of California, Berkeley, California, USA;

(2) U.S. Environmental Protection Agency, Washington, DC, USA

Address correspondence to T.J. Woodruff, Public Health and Environmental Policy Team, National Center for Environmental Economics, U.S. EPA, 75 Hawthorne St., MC SPE-1, San Francisco, CA 94105 USA. Telephone: [phone]. Fax: [phone]. E-mail: Woodruff. [e-mail]

We thank D. Axelrad, V.J. Cogliano, J. Gift, J. Jinot, and T. McKone for their expert technical assistance and advice.

This work was supported in part by grants from the U.S. EPA and the National Institute of Environmental Health Sciences (R826709 and ES09605). The views expressed in this article are those of the authors and do not necessarily reflect those of the U.S. EPA.

The authors declare they have no conflict of interest.

Received 2 January 2003; accepted 12 May 2003.