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NCEA Proposed Draft Charge to External Reviewers fo r the IRIS Toxicological Review of 1,2,4-Trimethylbenzene (1,2,4-TMB) and 1,3,5-Tri methylbenzene (1,3,5-TMB)

January 2012

Introduction

The U.S. Environmental Protection Agency (EPA) is s eeking an external peer review of the scientific basis supporting the draft Toxicological Review of 1,2,4-Trimethylbenzene (1,2,4- TMB) and 1,3,5-Trimethylbenzene (1,3,5-TMB) that wi ll appear on the Agency’s online database, the Integrated Risk Information System (I RIS). IRIS is prepared and maintained by the

EPA’s National Center for Environmental Assessment (NCEA) within the Office of Research and Development (ORD). There is currently no entry on the IRIS database for either 1,2,4-TMB or 1,3,5-TMB.

IRIS is a human health assessment program that eval uates qualitative and quantitative risk information on effects that may result from exposur e to specific chemical substances found in the environment. Through the IRIS Program, EPA provides quality science-based human health assessments to support the Agency’s regulatory acti vities. Combined with specific exposure information, government and private entities use IR IS to help characterize public health risks of chemical substances in site-specific situations in support of risk management decisions.

The external review draft Toxicological Review of 1 ,2,4-TMB and 1,3,5-TMB is based on a comprehensive review of the available scientific li terature on the human and animal health effects of 1,2,4-TMB and 1,3,5-TMB, and was develop ed according to general guidelines for risk assessment set forth by the National Research Counc il (1983) and guidelines and technical reports published by EPA (see Preface). This draft IRIS assessment provides an overview of the data regarding the toxicokinetics of 1,2,4-TMB and 1,3,5-TMB in humans and animals and characterizes the potential hazard posed by 1,2,4-T MB and 1,3,5-TMB exposure for noncancer and cancer health effects, including the derivation s of a chronic oral reference dose (RfD) and a chronic inhalation reference concentration (RfC) fo r both isomers. Additionally, the draft IRIS assessment includes a qualitative characterization of the human cancer potential for both

isomers.

Charge Questions

Below is a set of charge questions that address sci entific issues in the draft IRIS Toxicological Review of 1,2,4-TMB and 1,3,5-TMB. Please provide detailed explanations for responses to the charge questions. EPA will also consider the Scien ce Advisory Board reviewer panel comments on other major scientific issues specific to the ha zard identification and dose-response assessment of 1,2,4-TMB and 1,3,5-TMB. Please cons ider the accuracy, objectivity, and transparency of EPA’s analyses and conclusions in y our review.2

(A) General Charge Questions :

1. Is the Toxicological Review logical, clear and conc ise? Has EPA clearly presented and synthesized the scientific evidence for noncancer a nd cancer effects of 1,2,4-TMB and 1,3,5-TMB?

2. Please identify any additional peer-reviewed studie s from the primary literature that

should be considered in the assessment of noncancer and cancer health effects of 1,2,4- TMB and 1,3,5-TMB.

(B) Toxicokinetics and Pharmacokinetic (PBPK) Model ing

Data characterizing the toxicokinetics of 1,2,4-TMB and 1,3,5-TMB following inhalation and oral exposures in humans and experimental animals s upports the development of pharmacokinetic (PBPK) models for 1,2,4-TMB. For t he purposes of this assessment, the Hissink et al. (2007) model, originally describing 1,2,4-TMB toxicokinetics following exposure to white spirit (a complex mixture of volatile orga nic compounds), was modified to calculate internal dose metrics following exposure to 1,2,4-T MB alone. Additionally, the model was further modified by the addition of an oral route o f exposure for use in route-to-route extrapolations for the derivation of an oral RfD.

1. Does the selected PBPK model with EPA’s modificatio ns adequately describe the toxicokinetics of 1,2,4-TMB (Appendix A)? Was the PBPK modeling appropriately utilized and clearly described? Are the model assu mptions and parameters scientifically supported and clearly described? Are the uncertain ties in the model structure adequately

characterized and discussed?

2. The internal dose metric selected for use in the de rivation of the RfC and RfD was the steady-state weekly average venous blood concentrat ion (mg/L) of 1,2,4-TMB for rats exposed to 1,2,4-TMB for 6 h/day, 5 days/week. Ple ase comment on whether the selection of this dose metric is scientifically sup ported and clearly described. If a different dose metric is recommended for deriving t he RfC, please identify this metric and provide scientific support for this choice. Ar e the uncertainties in the selected dose metric adequately characterized and discussed?

(B) Inhalation Reference Concentration (RfC) for 1, 2,4-TMB

1. A 90-day inhalation toxicity study of 1,2,4-TMB in male rats was selected as the basis for the derivation of the RfC (Korsak and Rydzynski , 1996). Please comment on whether the selection of this study is scientifically suppo rted and clearly described. If a different study is recommended as the basis for the RfC, plea se identify this study and provide scientific support for this choice.

2. Decreased pain sensitivity (measured as increased l atency to pawlick response after hotplate test) in male Wistar rats was concluded by EP A to be an adverse effect on the central nervous system and was selected as the crit ical effect for the derivation of the3

RfC. Please comment on whether the selection of th is critical effect and its characterization is scientifically supported and cl early described. If a different endpoint is recommended as the critical effect for deriving the RfC, please identify this effect and provide scientific support for this choice.

3. Benchmark dose (BMD) modeling was used in conjuncti on with dosimetric adjustments for calculating the human equivalent concentration (HEC) from a rat and human PBPK model (Hissink et al., 2007) to estimate the point of departure (POD) for derivation of the RfC. Please comment on whether this approach is sc ientifically supported and clearly

described.

a) Has the modeling been appropriately conducted and c learly described, based on

EPA’s draft Benchmark Dose Technical Guidance Document (U.S. EPA, 2000b)? Has the choice of the benchmark response (BMR) for use in deriving the POD (i.e. a change equal to 1 SD of the estimated contr ol mean latency to pawlick response) been supported and clearly described?

4. Please comment on the rationale for the selection o f the uncertainty factors (UFs) applied to the POD for the derivation of the RfC for 1,2,4- TMB. Are the UFs appropriate and clearly described based on the recommendations desc ribed in A Review of the Reference Dose and Reference Concentration Processes (U.S. EPA, 2002)? If changes to the selected UFs are proposed, please identify and prov ide scientific support for the proposed changes.

(C) Inhalation Reference Concentration (RfC) for 1, 3,5-TMB

Two short-term neurotoxicity studies (Gralewicz and Wiaderna, 2001; Wiaderna et al., 2002) and one developmental toxicity study (Saillenfait e t al., 2005) following inhalation exposure to 1,3,5-TMB were identified in the literature and wer e considered as potential principal studies for the derivation of the RfC of 1,3,5-TMB. However, a n RfC was not derived for 1,3,5-TMB based

on these data for reasons described in the Toxicolo gical Review. The available toxicokinetic and toxicological databases for 1,2,4-TMB and 1,3,5-TMB indicate several similarities between the two isomers. Thus, EPA concluded that given the si milarities, including chemical properties, toxicokinetics, and potential toxicity between the two isomers, there was sufficient similarity to support adopting the RfC for 1,2,4-TMB for both iso mers.

1. Has the rationale for using the RfC for 1,2,4-TMB f or both isomers been clearly presented? Please comment on whether the approach is scientifically supported. Is the scientific justification for not deriving an RfC ba sed on the available data for 1,3,5-TMB supported and has it been clearly described?

(D) Oral Reference Dose (RfD) for 1,2,4-TMB

A route to route extrapolation from inhalation to o ral exposure using the modified Hissink et al. (2007) PBPK model has been used to derive a chronic oral RfD for 1,2,4-TMB. In order to4

perform the route-to-route extrapolation, an oral c omponent was added to the model, assuming a constant infusion rate into the liver. Specificall y, in the absence of chemical-specific information an assumption was made that 100% of the ingested 1,2,4-TMB was absorbed by

constant infusion of the oral dose into the liver c ompartment. The contribution of first-pass

metabolism was also evaluated.

1. The available oral studies for 1,2,4-TMB were deter mined to be inadequate for derivation of an RfD. Please comment on whether the justifica tion for the determination that the oral database is insufficient to support the deriva tion of an RfD for 1,2,4-TMB is clearly

described in the document and whether there are ava ilable data to support the derivation

of an RfD.

2. Has the PBPK modeling been appropriately utilized a nd clearly described? Are the model assumptions and parameters scientifically sup ported and clearly described? Are the uncertainties in the model structure adequately characterized and discussed? Please comment on whether this approach is scientifically supported and clearly described in the

document.

3. Please comment on the rationale for the selection o f the uncertainty factors (UFs) applied to the POD for the derivation of the RfD for 1,2,4- TMB. Are the UFs appropriate and clearly described based on the recommendations desc ribed in A Review of the Reference Dose and Reference Concentration Processes (U.S. EPA, 2002)? If changes to the selected UFs are proposed, please identify and prov ide scientific support for the proposed changes.

(E) Oral Reference Dose (RfD) for 1,3,5-TMB

The oral database for 1,3,5-TMB was determined to b e inadequate for derivation of an RfD. EPA concluded that given the similarities, includin g chemical properties, toxicokinetics, and toxicity between the two isomers, there was suffici ent similarity to support adopting the RfD for 1,2,4-TMB for both isomers.

1. Has the rationale for using the RfD for 1,2,4-TMB f or both isomers been appropriately and clearly presented? Please comment on whether t he current is scientifically supported and clearly described in the document and whether t here are available data to support the derivation of a 1,3,5-TMB-specific RfD.

(F) Carcinogenicity of 1,2,4-TMB and 1,3,5-TMB

1. Under EPA’s Guidelines for Carcinogen Risk Assessment (U.S. EPA, 2005a; www.epa.gov/iris/backgrd.html), the draft Toxicolog ical Review of 1,2,4-TMB and 1,3,5-TMB concludes that there is “inadequate infor mation to assess the carcinogenic potential” of 1,2,4-TMB and 1,3,5-TMB. Please comme nt on whether this characterization of the human cancer potential for 1,2,4-TMB and 1,3,5-TMB is scientifically supported and clearly described.5

2. The draft Toxicological Review of 1,2,4-TMB and 1,3 ,5-TMB did not derive a quantitative cancer risk estimate for 1,2,4-TMB and 1,3,5-TMB due to lack of available studies. Are there available data to support the de rivation of a quantitative cancer risk estimate for 1,2,4-TMB and 1,3,5-TMB? If so, please identify these data.