EPA’s Response to Major Interagency Comments on the Interagency Science Consultation 

Draft IRIS Toxicological Review of Trimethylbenzenes 

June 2012 

Purpose: The Integrated Risk Information System (IRIS) assessment development process of May 

2009 includes two steps (i.e., Steps 3 and 6b) where White House offices and other federal agencies 

can comment on draft assessments. The following are EPA’s responses to selected major 

interagency review comments received during the Interagency Science Consultation step (Step 3) 

for the draft IRIS Toxicological Review of Trimethylbenzenes. 

The Interagency Science Consultation draft Toxicological Review of Trimethylbenzenes (January 

2012) represents a significant advancement in implementing the 2011 recommendations from the 

National Research Council on the development of IRIS assessments1. Comments on the draft 

trimethylbenzenes (TMBs) assessment were received from the National Institute for Occupational 

Safety and Health (NIOSH), the National Institute of Environmental Health Sciences/National 

Toxicology Program (NIEHS/NTP), the Centers for Disease Control and Prevention/Agency for 

Toxic Substances and Disease Registry (CDC/ATSDR), Department of Defense (DOD), and Council 

on Environmental Quality (CEQ). In addition to the January 2012 draft, an abbreviated version of 

the Toxicological Review containing only information on 1,2,3-trimethylbenzene (1,2,3-TMB) was 

sent to interagency reviewers in May 2012 in response to their request (Topic # 7) that 1,2,3-TMB 

be added to the document. All interagency comments provided were taken into consideration in 

revising the draft assessment prior to posting for public comment and external peer review. The 

complete set of interagency comments is available on the IRIS website 

(http://www.epa.gov/ncea/iris). 

For a complete description of the IRIS process, including Interagency Science Consultation, visit the 

IRIS website at http://www.epa.gov/ncea/iris. 

Interagency Science Consultation Comments – Selected Major Comments and Responses: 

Topic #1: Consistency of elements of the Preamble with EPA Guidance – As for the recently 

released external peer review draft Toxicological Review of Ammonia (May 2012), the Toxicological 

Review of Trimethylbenzenes includes a new preamble that describes the application of existing EPA 

guidance and the methods and criteria used in developing IRIS assessments. The new preamble 

includes information on identifying and selecting pertinent studies, evaluating the quality of individual 

studies, weighing the overall evidence of each effect, selecting studies for derivation of toxicity values, 

and deriving toxicity values. DOD offered a series of comments asserting that elements of the draft 

1 National Research Council, 2011. Review of Environmental Protection Agency’s Draft IRIS Assessment of 

Formaldehyde. 

1 
 

 

 

 

 

 

 

preamble were inconsistent with EPA risk assessment guidelines, including: 1) none of the cited EPA 

guidelines suggests use of a “standard value” for a point of departure for extrapolation, much less 10% 

response for animal data and 1% for epidemiologic data (depending on the observed response rates) 

as stated in the preamble; 2) that EPA’s Cancer Guidelines differentiate low-dose extrapolation 

procedures for modes of action (MOAs) that are linear at low dose, MOAs that are nonlinear at low 

doses, and chemicals for which the MOA cannot be determined, but do not provide for a linear 

extrapolation where “the dose response curve is expected to have a linear component below the point 

of departure” as stated in the preamble; 3) that the following language from Section 7.4 of the draft 

preamble is not included in the cited guidelines: “Agents or their metabolites for which human 

exposures or body burdens are near doses associated with key events leading to an effect.”; and 4) that, 

contrary to the text of the preamble, the statement that “the agent does not demonstrate mutagenic or 

other activity consistent with linearity at lower doses” is not part of the criteria in EPA’s Cancer 

Guidelines for using a nonlinear extrapolation. Rather, DOD commented, the guidelines state that 

chemicals with a mutagenic MOA, not just mutagenic activity, are expected to have a linear 

extrapolation. 

EPA Response: In reference to point #1, for dichotomous data, EPA guidance recommends 

specific response levels for use across IRIS assessments to derive the point of departure (POD) 

for extrapolation. For example, EPA’s draft 2000 Benchmark Dose Technical Guidance Document 

states “the actual ‘benchmark dose’ used as a POD may correspond to response levels below (or 

sometimes above) 10%, although for convenience standard levels of 1%, 5%, or 10% have 

typically been used” (p. 19). Further, this guidance document states that “[a]n excess risk of 

10% has generally been the default BMR for quantal data” (p. 19) and that “epidemiology 

studies often have greater sensitivities and a BMR of 1% has typically been used for quantal 

human data” (p. 20). Similarly, EPA’s 2005 Guidelines for Carcinogen Risk Assessment (“Cancer 

Guidelines”) state that “[c]onventional cancer bioassays, with approximately 50 animals per 

group, generally can support modeling down to an increased incidence of 1–10%; 

epidemiologic studies, with larger sample sizes, below 1%” (p. 3-17). 

In recognition of the fact that selection of the response level used to derive a POD takes into 

consideration factors such as study design, sensitivity of the study, and nature or adversity of the 

effect, the text in Section 7.3 of the preamble was revised to better reflect those considerations. 

Although consistent values for response levels are generally used across IRIS assessments 

consistent with Agency guidance, EPA agreed that these response levels did not need to be 

characterized as “standard values” and revised the text of this section of the preamble accordingly. 

In reference to point #2, the text highlighted by DOD from Section 7.4 of the draft preamble is a 

quote from the Cancer Guidelines (p. 3-21). Since the language in the preamble is an accurate 

reflection of EPA guidelines, no changes to this part of the preamble were made. 

2 
3 

 

 

 

 

 

In reference to point #3, the text in Section 7.4 of the preamble is not an exact quote from EPA’s 

Cancer Guidelines (p. 3-21), but closely follows the wording in the Cancer Guidelines (provided 

below): 

Linear extrapolation should be used when there are MOA data to indicate that the 

dose-response curve is expected to have a linear component below the POD. Agents 

that are generally considered to be linear in this region include:... 

•	 Agents for which human exposures or body burdens are high and near doses 

associated with key precursor events in the carcinogenic process... 

The small changes to the text taken from the Cancer Guidelines were made only to more 

effectively and concisely capture the key points from the guidelines. 

In reference to point #4, the text highlighted by DOD from Section 7.4 of the draft preamble is a 

quote from the Cancer Guidelines (p. 3-22). Since the language in the preamble is an accurate 

reflection of EPA guidelines, no changes to this part of the preamble were made. 

Topic #2: Other suggested revisions to the Preamble – Other comments were offered by Federal 

agencies and CEQ to improve the clarity and completeness of the draft preamble. 

EPA response: EPA appreciated the input provided during the Interagency Science Consultation 

step and incorporated a number of the suggested revisions to the Preamble. 

Topic #3: Order in which PBPK modeling and BMD analysis was conducted for the 

derivation of the reference concentration (RfC) for 1,2,4-TMB – In the Interagency Science 

Consultation Draft, EPA conducted benchmark dose (BMD) analysis with external exposure 

concentrations as the dose inputs in order to identify a point of departure (POD). EPA then converted 

the identified POD into a human equivalent concentration (HEC) using the available PBPK model 

(Hissink et al., 2007). DOD expressed concern regarding the order of BMD/PBPK analysis in the draft 

Toxicological Review, stating that apparent nonlinearities between internal dose metrics and external 

exposure concentrations may have some impact on the calculation of the RfC. DOD stated that the 

more scientifically-defensible manner in which to conduct the BMD/PBPK analysis would be the 

following: 1) use the available rat PBPK model (Hissink et al., 2007) to calculate internal rat blood 

metrics; 2) perform BMD modeling using the estimated rat blood metrics as the dose inputs in order to 

identify a POD; and 3) use the available human PPBK model (Hissink et al., 2007) to calculate HECs 

from the identified rat PODs. 

EPA Response: In response to interagency comments, and after evaluation of the relationship 

between the PBPK model-estimated internal blood dose metrics and the external exposure 

concentrations at the individual PODs identified from toxicity studies, EPA agrees that the 
 

 

 

 

 

 

 

relationship between external concentrations and internal blood metrics is non-linear. EPA agrees 

that the most scientifically defensible methodology for conducting a BMD/PBPK analysis when 

non-linearity exists between internal doses and external concentrations is to convert external 

exposure concentrations into animal internal dose metrics and to use those metrics as the dose 

inputs for BMD modeling. Therefore, EPA has re-conducted the BMD/PBPK analysis for the 

derivation of the RfC for 1,2,4-TMB in the manner discussed above. 

However, one unforeseen consequence of performing the BMD/PBPK analysis in this order was the 

necessity of dropping the high dose in all modeling datasets. During the validation and optimization 

of the animal PBPK model (Hissink et al., 2007) against available animal kinetic datasets, the model 

accurately reproduced venous blood concentrations of 1,2,4-TMB following repeated (6 h/day, 

5d/week, 4 weeks) exposures to 123 or 492 mg/m3 (see Section B.3.3.2, Appendix B, PBPK Model 

Optimization and Validation). However, the model consistently overpredicted venous blood 

concentrations following exposure to 1230 mg/m3. EPA concluded that the optimized animal PBPK 

model produces acceptable simulations of venous blood 1,2,4-TMB concentrations for chronic 

exposures to 100 ppm (492 mg/m3) in rats following inhalation exposure to 1,2,4-TMB (see Section 

B.3.3.2., Appendix B). Therefore, as the model-estimated internal blood dose metrics at the high 

exposure concentration are not representative of empirically observed blood concentrations, using 

the high-dose model estimates as dose inputs for BMD modeling was not appropriate. 

Consequences of dropping the high dose are a loss of information regarding dose-response 

characteristics at high doses and a reduction in the number of available dose-response models to 

run against the datasets (due to the number of model parameters > dose groups). 

In the revised Toxicological Review, EPA has included a more thorough discussion of its modeling 

methodology, including detailed support and justification for conducting PBPK estimation of 

internal blood dose metrics first and BMD analysis using those internal metrics as dose inputs 

second. Additionally, EPA has provided a thorough discussion of the necessity of dropping the high 

dose in all modeling datasets due to poor PBPK model estimation of blood metrics at the high dose. 

In Appendix C, Dose-Response Modeling for the Derivation of Reference Values for Effects Other than 

Cancer and Cancer Risk Estimates, EPA has included alternative modeling results when the high 

doses were not dropped for comparison purposes only. These modeling results were not used in 

any reference value derivation. 

Topic #4: Selection of the Principal Study and Critical Effect for derivation of the RfC for 

1,2,4-TMB – The inhalation database for 1,2,4-TMB contains three subchronic studies investigating 

the neurological, respiratory, hematological, and developmental toxicity of 1,2,4-TMB in Wistar rats 

(Korsak et al., 2000; Korsak et al., 1997; Korsak and Rydzyński, 1996). EPA selected Korsak and 

Rydzyński (1996) as the principal study and decreased pain sensitivity as the critical effect on which to 

base the derivation of the RfC for 1,2,4-TMB. Decreased pain sensitivity was selected as the critical 

4 
 

 

 

effect based on the consistency of observation of this effect across multiple studies of acute, short-term, 

and subchronic durations (Gralewicz and Wiaderna, 2001; Gralewicz et al., 1997; Korsak and 

Rydzyński, 1996; Korsak et al., 1995) and the determination that this effect is adverse in accordance 

with EPA’s Guidelines for Neurotoxicity Risk Assessment (1998). DOD noted that decreased pain 

sensitivity was observed to be reversible following termination of exposure, and raised concerns 

regarding the appropriateness of using a reversible outcome for derivation of the RfC. DOD 

commented that the uncertainties and limitations of the Korsak and Rydzyński (1996) were not 

appropriately discussed in the Toxicological Review. 

EPA Response: Although the observation of decreased pain sensitivity in the Korsak and 

Rydzyński (1996) study was observed to be reversible, the ability of exposed animals to recover 

following termination of exposure does not discount this effect from consideration for derivation of 

an RfC. In particular, EPA’s Guidelines for Neurotoxicity Risk Assessment (1998) state that neurotoxic 

effects that are slowly reversible are of high concern, while effects that are quickly reversible or 

“transient” relative to the toxicokinetics of the chemical are of “less” concern (although the 

guidelines do not state that rapidly reversible effects are of no concern). 

Kinetic studies in rats and humans indicate that metabolic clearance of TBM isomers from the blood 

and organs is rapid (on the order of hours in rats or up to 3 days in humans). Observations in 

toxicity studies (e.g., Gralewicz et al. (1997)) demonstrate treatment-related effects on pain 

sensitivity up to 50-51 days following termination of exposure, indicating that the presence of 

neurotoxicity is not related to the presence of TMB in the blood of exposed animals. Therefore, 

neurotoxic effects appear to be persistent following the rapid metabolic clearance of TMB. In 

accordance with EPA’s Guidelines for Neurotoxicity Risk Assessment (1998), these effects would be of 

“high concern” and are therefore appropriate for derivation of RfC values. 

Clarifying text has been added to the Hazard Identification and Dose-Response Analysis sections of 

the Toxicological Review specifically describing the reversibility of pain sensitivity in the Korsak 

and Rydzýnski (1996) study and why, in accordance with EPA’s Guidelines for Neurotoxicity Risk 

Assessment (1998), EPA concluded that this effect was appropriate for selection as a potential 

critical effect for derivation of the RfC. 

Topic #5: Selection and application of the uncertainty factors for the derivation of the RfC 

for 1,2,4-TMB and 1,3,5-TMB – In deriving the RfCs for 1,2,4-TMB and 1,3,5-TMB, EPA applied a 

composite uncertainty factor (UF) of 1,000 to the HECs calculated with the available PBPK model 

(Hissink et al., 2007). This composite UF was comprised of the following individual UFs: a 3-fold UFA to 

account for residual toxicodynamic differences between animals and humans, a 10-fold UFH to account 

for human variability, a 10-fold UFS to account for extrapolation from a subchronic study to a chronic 

reference value, and a 3-fold UFD to account for deficiencies in the toxicity database. DOD provided 

extensive comments on EPA’s selection and application of UFs, including: 1) that UFs should be applied 

5 
 

 

 

 

 

 

to the internal dose metric calculated by the PBPK model (Hissink et al., 2007) before any intraspecies 

extrapolations; 2) the available PBPK model (Hissink et al., 2007) could be used to perform a 

sensitivity analysis in order to inform the selection of the UFH; 3) the database uncertainty factor 

should be decreased to 1 as the lack of multigenerational reproductive/developmental toxicity study is 

unlikely to result in a lower POD; 4) the composite uncertainty of 10,000 applied to the 1,3,5-TMB 

short-term neurotoxicity effects should be reduced to 3,000; and 5) EPA should more thoroughly 

discuss and integrate the strengths and limitations of the toxicity database. 

EPA Response: In the revised Toxicological Review, uncertainty factors are applied to the human 

equivalence concentration calculated using the available human PBPK model (Hissink et al., 2007). 

Uncertainty factors were applied in this manner based on the recommendation of EPA methods 

reports: A Review of the Reference Dose and Reference Concentration Processes (2002) and Methods 

for Derivation of Inhalation Reference Concentrations and Application of Inhalation Dosimetry 

(1994). The available PBPK model (Hissink et al., 2007) was used to conduct a sensitivity analysis 

of the human internal dose metric near the POD to identify the model parameters that have an 

impact on model estimates. The results of this sensitivity analysis (included in Section B.3.3.4 

(Sensitivity Analysis of Human Model Predictions)) indicate that the two fitted metabolic parameters, 

VmaxC and Km both influence model predictions and are considered moderately sensitive (absolute 

value of the normalized sensitivity coefficient between 0.2 and 1.0). The sensitivity analysis did not 

provide sufficient information to reduce the current 10-fold UFH. 

The purpose of the database uncertainty factor, as defined by EPA’s A Review of the Reference Dose 

and Reference Concentration Processes (2002) is “to account for the potential for deriving an 

underprotective RfD/RfC as a result of an incomplete characterization of the chemical’s toxicity”. In 

this regard, consideration of a study’s duration and the potential for greater effects in chronic 

studies vs. subchronic studies should be accounted for in the subchronic to chronic uncertainty 

factor. EPA has removed any mention of the lack of a chronic study in the text justifying the 

selection of the database uncertainty factor. EPA’s A Review of the Reference Dose and Reference 

Concentration Processes (2002) states that reproductive and developmental toxicity studies are 

often useful in determining the lowest NOAEL for a study and that application of an uncertainty 

factor is justified when either of these study types are missing. Although the Saillenfait et al. (2005) 

study did not observe overt developmental toxicity in the form of embryonic/fetal lethality or 

teratogenicity, it did observe statistically significant decreases in male and female fetal weight. 

Further, although no reproductive toxicity studies of 1,2,4-TMB are available, a study investigating 

the reproductive and multigenerational developmental effects of high flash naphtha (McKee et al., 

1990) observed effects at doses in the F3 generation that were lower than doses that elicited effects 

in the F2 or F1 generations. As high flash naphtha contains TMB isomers, this raises concerns that 

the multigenerational reproductive/developmental toxicity of 1,2,4-TMB may occur at lower doses 

than reported by Saillenfait et al. (2005). 

6 
 

 

 

 

 

However, as developmental effects in the Saillenfait et al. (2005) study were observed at levels 

much higher than those eliciting toxicities in adult animals (Korsak studies), there is some doubt 

whether inclusion of a multigenerational study in the toxicity database would identify the lowest 

POD for 1,2,4-TMB. EPA’s Review of the Reference Dose and Reference Concentration Processes 

(2002) also recommends that the database uncertainty factor take into consideration if there is 

concern from the available toxicology database that developing organisms may be particularly 

susceptible to effects in specific organ systems. TMB is able to cross the placenta (Cooper et al., 

2001; Dowty et al., 1976); therefore, as neurotoxicity is observed in adult animals, there exists the 

concern that TMB may result in neurotoxicity in the developing organism. Effects in adult animals 

(motor activity and cognitive function) are reported by EPA’s Guidelines for Neurotoxicity Risk 

Assessment (1998) as effects that can specifically impact the developing organism. EPA’s Guidelines 

for Neurotoxicity Risk Assessment (1998) also indicate that neurotoxicants may have greater access 

to the nervous system in developing organisms due to the an incomplete blood-brain barrier and 

before metabolic detoxifying pathways are fully formed. Therefore, there is some concern that the 

inclusion of a developmental neurotoxicity study could potentially result in a lower POD identified 

from the TMB toxicity database, and therefore, a lower RfC would be derived. Section 2.1.3 (RfC 

Derivation for 1,2,4-TMB) has been revised to include a thorough discussion regarding the selection 

and justification of the database uncertainty factor for the derivation of the 1,2,4-TMB RfC. 

Regarding the calculation of the 10,000-fold composite uncertainty factor for the effects observed 

in the short-term 1,3,5-TMB toxicity studies, EPA concluded that this composite uncertainty factor 

is appropriate. The database uncertainty factor for this database remains the same as the database 

uncertainty factor for 1,2,4-TMB. Given the observation of developmental effects and neurotoxicity 

in adult animals, there remains some concern due to the lack of a developmental neurotoxicity 

study. For this reason, the database uncertainty factor of 3 was retained in the document. 

EPA agrees that the strengths and limitations of the TMB toxicity database should be discussed 

more thoroughly and integrated into the text describing and justifying the selection of the database 

uncertainty factor. The limitations and strengths of the database have been thoroughly discussed in 

more detail in the appropriate sections of the document, specifically addressing the issues 

discussed above (i.e., lack of a multigenerational reproductive/developmental toxicity study and 

the concern associated with the lack of a developmental neurotoxicity). 

Topic #6: Selection of the benchmark response (BMR) for the derivation of the RfC for 1,2,4-

TMB – In deriving the RfC for 1,2,4-TMB in the Interagency Science Consultation draft assessment, 

EPA selected a BMR of 5% decrease from the control mean in fetal body weight to identify a POD, 

based on the determination that such a decrease in fetal body weight represents a minimal, 

biologically significant change. DOD commented that EPA provided limited support for this 

7 
 

 

 

 

 

determination, and requested that EPA provide a clear rationale for the decision to use 5% decrease in 

body weight as the BMR. 

EPA Response: In response to interagency comments, EPA has included further discussion of the 

biological justifications for selection of a BMR of 5% decrease from the control mean for fetal 

weight effects. EPA has concluded that this response level is a biologically significant response for 

fetuses in the Saillenfait et al. (2005) study for the following reasons: 1) decreased body weight 

gain in fetuses and/or pups is considered indicative of altered growth which is identified as one of 

the four major manifestations of developmental toxicity (U.S. EPA, 1991), a decrease in 10% body 

weight is generally recognized as a biologically significant response in adult animals associated 

with identifying a maximum tolerated dose; 3) fetuses and/or pups are generally recognized as a 

susceptible lifestage and are assumed to be more greatly affected by decreased body weight than 

adults; and 4) in humans, reduced birth weight is associated with (but not limited to) neonatal and 

postnatal mortality, coronary heart disease, arterial hypertension, chronic renal insufficiency, and 

diabetes mellitus (Barker, 2007; Reyes and Mañalich, 2005). Therefore, the selection of a BMR of 

5% was considered a reasonable and biologically significant response level, and was used in the 

BMD modeling of fetal weight endpoints. 

Topic #7: Exclusion of 1,2,3-TMB from the Toxicological Review – The January 2012 

Interagency Science Consultation draft assessment contained information on two of the three possible 

TMB isomers, 1,2,4-TMB and 1,3,5-TMB; derivation of human health reference values was limited to 

these two isomers. A third TMB isomer, 1,2,3-trimethylbenzene (hemimellitene), is present in some 

mixtures containing trimethylbenzenes. DOD, CDC/ATSDR, NIEHS/NTP, and CEQ commented that it 

was unclear why EPA decided not to include 1,2,3-TMB in the assessment, and suggested that inclusion 

of this isomer may be beneficial to users. These reviewers requested that a more thorough discussion of 

the rationale for not including 1,2,3-TMB should be included in the Toxicological Review. 

EPA Response: EPA agrees that the inclusion of the 1,2,3-TMB isomer in the assessment would 

likely be beneficial to users. Therefore, 1,2,3-TMB has been added to the document, including a full 

integration in the Toxicological Review of Hazard Identification information in Section 1, and RfC 

and RfD derivations included in Section 2. 

Topic #8: Development of a PBPK model for 1,3,5-TMB – In the Interagency Science 

Consultation draft assessment, EPA states that there is currently no PBPK model for 1,3,5-TMB that is 

parameterized for rats or humans. DOD commented that EPA should provide an explanation why a 

1,3,5-TMB PBPK model was not adapted from the available 1,2,4-TMB model (Hissink et al., 2007). 

DOD indicated that development of a 1,3,5-TMB PBPK model would be relatively easy given the 

existence of the 1,2,4-TMB PBPK model, and development of a model would be consistent with previous 

EPA Toxicological Reviews that either developed models de novo or heavily modified existing models. 

Although development of a PBPK model for 1,3,5-TMB would represent a substantial level of effort, 

8 
DOD felt it was an appropriate exercise if it resulted in a reduction of uncertainty in the draft 

assessment. 

EPA Response: In the draft assessment, the RfC and RfD for 1,3,5-TMB are adopted from those 

derived from 1,2,4-TMB. This is due to a lack of suitable 1,3,5-TMB toxicity data on which to derive 

chronic reference values. Therefore, the utility of a PBPK model specifically addressing 1,3,5-TMB is 

questionable. However, in response to DOD’s comments that development of a 1,3,5-TMB PBPK 

model should be relatively easy given the existing 1,2,4-TMB PBPK model and similar kinetics, EPA 

investigated model development for 1,3,5-TMB. The 1,2,4-TMB parameterized rat and human PBPK 

model was tested for its ability to predict 1,3,5-TMB venous blood concentrations reported in the 

literature. Validating the model against data from Swiercz et al. (2006), the model predicted the rat 

venous blood concentration following single or re

3 

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o 492 mg/m 1,3,5-TMB well; 

however, the model overpredicted the 123 mg/m and 1,230 mg/m exposure da

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ta for rats. In 

validating the model against data from Kostrewski et al. (1997), the model underestimated peak 

venous blood concentration following an 8 hr exposure to 150 mg/m 1,3,5-TMB in humans by 

about 30%; however, model prediction of 1,3,5-TMB clearance from t

3 

he blood was very good. 

Therefore, EPA concluded that the 1,2,4-TMB PBPK model would need reparameterization in order 

to better characterize the observed kinetics of 1,3,5-TMB. This effort was not considered to be 

warranted at this time. 

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