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Draft Charge to External Review ers for the IRIS Toxicological Review of Dichloromethane

December 2009

The U.S. Environmental Protection Agency (EPA) is seeking an external peer review of the scientific basis supporting the human health assessment of dichl oromethane that will appear on the Agency ’ s online database, the Integrated Risk Information System (IRIS). IRIS is prepared and maintained by the EPA ’ s National Center for Environmental Assessment (NCEA) within the Office of Research and Development (ORD ). An existing IRIS assessment of dichloromethane was posted to the database in 1987 ; the cancer assessment was updated in 1990

.

The current draft health assessment includes a chronic r eference d ose (RfD) and r eference

c oncentration (RfC) and a carcinoge nicity assessment. Below is a set of charge questions that address scientific issues in the assessment of dichloromethane. Please provide detailed explanations for responses to the charge questions.

General Charge Questions:

1. Is the Toxicological Rev iew logical, clear and concise? Has EPA clearly synthesized the

scientific evidence for noncancer and cancer hazard?

2. Please identify any additional studies that would make a significant impact on the conclusions of the Toxicological Review and should be considered in the assessment of the noncancer and

cancer health effects of dichloromethane.

Chemical

- Specific Charge Questions:

(A) PBTK Modeling

1. A rat PBTK model was used for calculating the internal dosim etry for the RfC and RfD .

E PA evaluated several versions of previously published rat PBTK models and selected the Andersen et al. (1991) model for use in these calculations

.

a. Does the chosen model a dequately represent the toxicokinetics? Was the model applied properly? Are the model as sumptio ns and parameters clearly presented and scientifically supported? Are the uncertainties in the model structure a ppropriately

considered and discussed?

b. The internal dose metric used in the RfD and RfC derivations was based on total hepatic metabolism throu gh the CYP2E1 pathway. Because the metric is a rate of metabolism, and the clearance of metabolites is expected to be slower in the human compared with the rat (assuming clearance scales as BW 3/4 ), the rat internal dose metric is adjusted by dividing by a pharmacokinetic scaling factor to obtain a

human

- equivalent internal dose

. ? Are the choices of dose metric and toxicokinetic scaling factor appropriate? Is the rationale for these choices transparently and objectively described?

2. The mouse PBTK model used in deriving the cancer toxicity values was based on the2

published work of Marino et al. (2006).

a. Does the chosen model a dequately represent the toxicokinetics? Was the model applied properly? Are the model as sumptions and parameters clearly presente d and scientifically supported? Are the uncertainties in the model structure appropriately

considered and discussed?

b. Please comment on the application of the metabolism

- based dose metrics in the PBTK modeling for the cancer quantitation. Specifically, pl ease comment on the scientific rationale in choosing the tissue

- specific GST

- metabolite dose metric and the application of a toxicokinetic scaling factor to account for potential clearance

rate differences between humans and animals

3. For the RfD and RfC d erivations, a human PBTK model (David et al., 2006) was used to estimate human equivalent doses from internal rat liver doses. For the derivation of cancer toxicity values, th e human PBTK model was used to calculate the distribution of human

internal dose metrics of dichloromethane metabolized via the tissue

- specific (i.e. liver or lung) GST pathway per unit volume of tissue.

a. Is the rationale for the human parameter estimates scientifically justified and transparently and objectively described? Have th e modifications in the model parameters accounted for population variability and parameter uncertainty in estimating human equivalent doses? Are these modifications scientifically supported?

b. Do these parameter values represent the optimal choice, give n th e current state of knowledge? Are the uncertainties in these parameters appropriately considered

and discussed?

(B). Noncancer T oxicity of D ichloromethane

Oral reference dose (RfD) for dichloromethane

1. A chronic RfD for dichloromethane has been de rived from a 2

- year oral (drinking water) study in the rat (Serota et al

. , 1986a). Please comment on whether the selection of this study as the principal study is scientifically justified.

2. An increase in the incidence of nonneoplastic liver lesions (foci/areas of alteration) was selected

as the critical effect for the RfD . Please comment on whether the selection of this critical effect is scientifically justified. Please identify and provide the rationale for any other endpoints that should

be consi dered in the selection of the critical effect.

3. Benchmark dose (BMD) modeling methods were applied to the nonneoplastic liver lesion data to derive the point of departure (POD) for the RfD. Has the BMD modeling been appropriately

conducted? Is the ben chmark response (BMR) selected for use in deriving the POD (i.e., a 10% increase in incidence of liver lesions) scientifically justified?

4 . Please comment on the rationale for the selection of the uncertainty factors (UFs) applied to the

POD for the de rivation of the RfD. If changes to a UF are proposed, please identify and provide3

a rationale(s).

Inhalation reference concentration (RfC) for dichloromethane

5 . A chronic RfC for dichloromethane has been derived from a 2

- year inhalation bioassay in r ats (Nitschke et al., 1988a). Please comment on whether the selection of this study as the principal study is scientifically justified.

6 . Hepatic vacuolation was selected as the critical effect for the RfC. Please comment on whether

the selection of this critical effect is scientifically justified. Please identify and provide the rationale for any other endpoints that should be considered in the selection of the critical effect.

7 . BMD methods were applied to incidence data for hepatic vacuolation t o derive the POD for the

RfC. Has the BMD modeling been appropriately conducted? Is the BMR selected for use in deriving the POD (i.e., a 10% increase in incidence of hepatic vacuolation) scientifically justified?

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. Please comment on the rationale for the selection of the UFs applied to the POD for the

derivation of the Rf

C

. If changes to a UF are proposed, please identify and provide a rationale(s).

( C ) Carcinogenicity of D ichloromethane

1. Under the EPA ’ s 2005 Guidelines for Carcinogen Risk Asse ssment (www.epa.gov/iris/backgr

d.htm), dichloromethane is likely to be carcinogenic to humans by all routes of exposure. Please comment on the cancer weight of evidence characterization. Is the cancer weight of evidence characterization scientifically j ustified and clearly described ?

2. A mutagenic mode of carcinogenic action is proposed for dichloromethane

. Please comment on whether the weight of the scientific evidence supports this conclusion. Please comment on whether the analysis is scientificall y justified and clearly described

. Please comment on data available for dichloromethane that may support an alternative mode of action.

Quantitative cancer assessment

- oral exposure

3

. A two

- year drinking water study (Serota et al., 1986b) was selecte d for the derivation of an oral slope factor (OSF) for dichloromethane

. Please comment on whether the selection of this study for quantification

is scientifically justified.

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. The OSF

was calculated by linear extrapolation from the POD (lower 95% conf idence limit on

the dose associated with 10% extra risk for mouse liver tumors). The OSF is based on the analysis of the most sensitive of the subgroups, the GST

- T1 +/+ genotype, using mean internal dose predictions for that subgroup. Please comment on t he adequacy of this approach, including the choice of tumors and the manner in which the modeling was conducted.

Quantitative cancer assessment

- inhalation exposure4

5

. A two

- year cancer bioassay (NTP, 1986) was selected for the derivation of an inhal ation unit risk (IUR) for dichloromethane. Please comment on whether the selection of this study for quantification

is scientifically justified.

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. The IUR was calculated by linear extrapolation from the POD ( using a BMR of 10% extra risk

for mouse liv er and lung tumors) and by determining the upper bound on the combined central tendency IURs for male lung and liver tumors. T he IUR is based on the analysis of the most sensitive of the subgroups, the GST

- T1 +/+ genotype, using mean internal dose predict ions for that subgroup. Please comment on the adequacy of this approach, including the choice of tumors and the manner in which the modeling was conducted