Case Study #13 – Apply AEGL Methodology to Develop Acute ...



Beyond Science and Decisions: From Issue Identification to Dose-Response Assessment:

Summary of Case Study #25: Deriving Health-Protective Values for Evaluation of Acute Inhalation Exposures for Chemicals with Limited Toxicity Data Using a Tiered Screening Approach

Grant R.L., Phillips T., Ethridge S., Toxicology Division, Texas Commission on Environmental Quality, Austin, TX

1. Provide a few sentences summarizing the method illustrated by the case study.

On an interim basis during the air permit review process, the Toxicology Division (TD) from the Texas Commission of Environmental Quality (TCEQ) frequently evaluates chemicals with limited toxicity data (LTD chemicals). A tiered approach is used to either set a default Effects Screening Level (ESL) or derive a generic health-based ESL depending on the availability of toxicity information and time and resource constraints (Section 3.6 of TCEQ 2006):

• Tier I – Threshold of Regulation (default ESL = 1 µg/m3)

• Tier II – Threshold of Concern and Use of a NOAEL-to-LC50 Ratio (generic ESL)

• Tier III – Relative Toxicity/Potency Approach (generic ESL)

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Figure 3-2. A three-tiered approach to setting a default or a generic health-based ESL (TCEQ 2006)

This case study reviews the procedures used to set health-protective concentrations for LTD chemicals based on a Tier II approach, using pentene isomers as example chemicals. For the Tier II approach, acute inhalation lethality data are required. Basically, the statistical approach used to establish the Tier II approach is based on the assumption that the dose-response assessment is a threshold, nonlinear dose response (i.e., identify an appropriate point of departure and apply uncertainty factors). Sections 3.6.1 and 3.6.3 of the TCEQ ESL Guidelines (TCEQ 2006) provides additional information on the Tier I - Threshold of Regulation Approach (no toxicity data is required) and Tier III - Relative Toxicity/Potency Approach, respectively. A Relative Toxicity/Potency Approach requires additional time and resources because toxicity data and physical/chemical properties from structurally related chemicals must be obtained, then a comparison of the toxicity of these structurally related chemicals to the LTD chemical is performed. The Sustainability Futures Case Study also discusses a Relative Toxicity Approach.

In the Threshold of Concern (TOC) approach (Grant et al. 2007), acute inhalation lethality data are used to classify chemicals in different acute toxicity categories based on the Globally Harmonized System of Classification and Labeling of Chemicals (GHS) proposed by the United Nations (UN 2005). Refer to Table 1 of Grant et al. (2007) for the GHS system and corresponding LC50 data ranges for the different GHS categories. The following health-protective concentrations are used for chemicals assigned to different GHS categories: 4 µg/m3 for chemicals classified in Category 1; 20 µg/m3 for Category 2; 125 µg/m3 for both Categories 3 and 4; and 1000 µg/m3 for Category 5. Refer to Grant et al. (2007) for a discussion of how these health-protective values for each GHS category were derived. Pentene was classified in Category 5 based on LC50 data in both rats and mice so the generic screening level was 1000 µg/m3 (page 5 of the pentene Development Support Document (DSD) (TCEQ 2007)).

For the NOAEL-to-LC50 ratio approach (N-L ratio approach) (Grant et al. 2007), a 4-hr duration LC50 value was multiplied by a factor of 8.3 x 10-5 to estimate health-protective air concentrations. Refer to Grant et al. (2007) for a discussion of how this N-L ratio composite factor was derived. For pentene, the lowest 4-hr duration LC50 data was 90,000,000 µg/m3 so the generic ESL was 7,500 µg/m3 (pages 5-6 of the pentene DSD (TCEQ 2007)).

2. Describe the problem formulation(s) the case study is designed to address. How is the method described in the case useful for addressing the problem formulation?

ESLs are chemical-specific air concentrations set to protect human health and welfare and are used in the air permitting process to assess the protectiveness of emission rate limits. Short-term ESLs are developed to evaluate acute intermittent exposures of one hour (hr) whereas long-term ESLs are developed to evaluate chronic exposures. The Texas Health and Safety Code is comprehensive. Therefore, ESLs are developed for as many air contaminants as possible, even for chemicals with limited toxicity data.

The Texas Clean Air Act (Chapter 382 of the Texas Health and Safety Code) authorizes the TCEQ to conduct air permit reviews of all new and modified facilities to ensure that the operation of a proposed facility will not cause or contribute to a condition of air pollution. Air permit reviews typically involve evaluations of best-available-control technology and predicted air concentrations related to proposed residual emissions from the new or modified facility. In a conservative evaluation, worst-case emission rates are modeled to predict resulting short-term and long-term chemical-specific maximum ground level air concentrations (GLCmax). In the review of proposed emissions, chemical-specific ESLs developed by TCEQ toxicology staff are used for non-criteria pollutants. The TCEQ and other regulators need to develop conservative, health-protective concentrations for chemicals with limited toxicity data for the review of short-term GLCmaxs taking into consideration that ambient air exposure is dependent on meteorological conditions and peak exposures that could occur several times per day. If the GLCmax, a worst case concentration resulting from a worst case emission rate, is below the generic ESL for that chemical, the substance can be judged, with reasonable confidence, to present a low probability of risk.

The method described in the case study is useful for addressing the problem formulation because the use of the TOC approach or composite factor N–L ratio approach can be used on an interim basis until additional acute toxicity information becomes available for a chemical if a chemical has limited acute inhalation toxicity information.

3. Comment on whether the method is general enough to be used directly, or if it can be extrapolated, for application to other chemicals and/or problem formulations. Please explain why or why not.

This method can be used by others who need to develop acute inhalation screening values protective of a 1-hr intermittent exposures for chemicals with LTD. This specific method should only be used for chemicals with LTD, not chemicals with adequate toxicity information and should mainly be used to evaluate proposed residual emissions. The acute inhalation database contained both inorganic and organic compounds, but did not contain metallics, nerve gases, or non-structurally defined substances (such as gums, resins, oils, etc.), so the method is not applicable for these compounds.

This method can be used for other problem formulations. For instance, in some cases, toxicity information is not available for an exposure duration of 24 hrs or less, but data is available for a chemical from a well-conducted short-term study lasting from 1 day to 4 weeks. The TCEQ uses the experimental data from the short-term study when it is justified by the MOA analysis. If a short-term study is used to derive an ESL used for evaluation of a 1-hr exposure duration, a comparison to a generic ESL derived based on procedures discussed in Section 3.6 will be conducted to ensure the derived value is not overly conservative. In some cases, the short-term study may be used as supporting information for a generic ESL.

The statistical methods and approaches used to develop the TOC and N-L ratio approach were originally designed to evaluate oral exposure (reviewed in Sections 1.1 and 1.2, respectively (Grant et al. 2007)). These statistical methods/approaches can be used for other routes of exposure or other exposure durations, if an adequate database of animal NOAELs or LC50 data can be obtained.

4. Discuss the overall strengths and limitations of the methodology.

There are several overall strengths to this methodology. First and foremost, this methodology uses a statistical analysis of a compiled database of LC50 and NOAEL data to establish a generic approach for determining health-protective concentrations for chemicals with limited toxicity data (Grant et al. 2007). A validation exercise was performed to ensure the approach was predictive and health-protective (refer to Table 4 and Sections 3.4 and 3.5 of Grant et al. 2007). The estimated generic ESLs were compared to the published acute toxicity factors for the database chemicals. Based on the validation exercise, use of the TOC or N-L ratio approaches should be health-protective because there is less than a 10% probability that toxicological studies of any other substance not included in the database would result in a N-L ratio or TOC concentration lower than the tenth percentile.” (Grant et al. 2007).

This is a conservative method for predicting generic health-protective concentrations using acute lethality data. Typically LC50 data is available for chemicals with limited toxicity information; this methodology allows a conservative screening value to be developed based on the LC50 data for those chemicals.

For this methodology, two approaches are offered; threshold of concern (TOC) and a N-L ratio approach. A weight of evidence is used to decide which approach is most appropriate. For pentene, the chemical structure indicated that it was relatively nontoxic, so the less conservative value based on the N-L ratio approach of 7,500 µg/m3 was chosen instead of the value of 1000 µg/m3 based on the TOC approach. (page 6 of Pentene DSD (TCEQ 2007)).

In turn, since this method is conservative, if an interested party believes the generic value is too low, this method could prompt them to consider performing toxicity tests to improve the toxicity information available for a chemical, which would then allow a more comprehensive toxicity assessment to take place. Since this methodology is developed for use for chemical with limited toxicity information, it can be used on an interim basis until more toxicity information becomes available for those chemicals. As mentioned previously, this method may also be used as a check for health-protective values derived from short-term studies; this comparison may be done to ensure the derived value is not overly conservative (i.e., lower than the conservative, generic value).

As with most methodologies there are also limitations. Since the acute inhalation database did not contain metallics, nerve gases, or non-structurally defined substances (such as gums, resins, oils, etc.), the method is not applicable for these compounds. A main limitation is that this methodology is only for one-hr intermittent inhalation exposure. Also, since inhalation toxicology studies are more difficult and expensive to conduct than oral studies, the database used to derive the method consists of only 97 chemicals. Another limitation is that if toxicity data were available for a LTD chemical, the health-protective value based on actual toxicity data could be less than the TOC or N-L ratio derived value, (meaning that the derived value would not be health protective in these cases), although there is less than a 10% probability that would occur. Finally, the TOC approach for inhalation data is based on LC50 data. If LC50 data are not available, then a Relative Toxicity/Potency Approach must be used.

5. Outline the minimum data requirements and describe the types of data needed.

In the TOC approach, acute lethality data are used to classify chemicals in different acute toxicity categories (TC) based on the GHS proposed by the United Nations (UN 2005) (refer to Table 1 of Grant et al. 2007). For the N-L ratio approach, acute inhalation lethality data are multiplied by a tenth percentile composite factor N-L ratio to estimate health-protective air concentrations. The first step for both approaches is selection of scientifically-defensible acute lethality data using the criteria described in Section 2.4 and Figure 1 of Grant et al. (2007).

HOW THIS ASSESSMENT ADDRESSES ISSUES RAISED IN SCIENCE & DECISIONS:

A. Describe the dose-response relationship in the dose range relevant to human exposure.

Basically, the statistical approaches used to establish the Tier II approach is based on the assumption that the dose-response assessment is a threshold, nonlinear dose response (i.e., identify an appropriate point of departure and apply uncertainty factors). Animal NOAELs are used in both approaches to which a composite uncertainty factor (UF) of 100 is applied to account for animal-to-human extrapolation uncertainty and human variability to establish a conservative health-protective air concentration below which no appreciable risk to human health would be expected to occur (Figure 3 and Table 3 for the TOC approach and Figure 4 and Table 5 for the N-L ratio composite factor approach (Grant et al. 2007)).

B. Address human variability and sensitive populations?

For the TOC approach, the 10th percentile of NOAELs from animal studies were calculated. For the N-L ratio approach, the 10th percentile of the N-L ratio for 55 chemicals were calculated. An UFH of 10 was applied to these values to calculate the 10th percentile composite factor specifically to address human variability and sensitive populations.

C. Address background exposures and responses?

These methods do not directly address background exposures or responses in people.

D. Address incorporation of existing biological understanding of the likely mode of action (MOA)?

For chemicals with limited toxicity data, mode of action information is not available. In general, development of generic ESLs for acute exposures assume that the evaluated non-cancer adverse effects have a threshold mode of action. However, the inhalation database for the 97 chemicals contained a variety of different critical effect endpoints that had different MOAs (respiratory tract, irritation, dermal/ocular/mixed, neurological, developmental, hematological, hepatic or renal, and cardiac), although 48% of the inhalation studies produced point of entry effects such as irritation, respiratory tract, or dermal/ocular effects (Table 6 of Grant et al. (2007)).

E. Address other extrapolations, if relevant – insufficient data, including duration extrapolations, interspecies?

Typically interspecies variability is addressed by the use of an interspecies uncertainty factor (UFA) of 10 that is applied to the animal NOAELs (TOC approach) or applied to the N-L ratio (N-L ratio approach). An UFA of 10 was used in conjunction with an UFH of 10 to calculate the 10th percentile composite factor.

Use of the 10th percentile composite factor of the cumulative distribution of data is a conservative approach.

As far as duration extrapolations, LC50 values are adjusted to correspond to a 4-hr exposure duration using Haber’s Law as modified by ten Berge (1986) because inhalation cut-off values for the GHS categories are based on 4-hr testing exposures (UN 2005). LC50 data were duration adjusted to correspond to a 4-hr exposure duration; however, duration adjustments were not applied to the NOAELs in the database. This is a conservative approach since 90% of the inhalation toxicity data were from studies greater than or equal to a 1-hr exposure.

F. Address uncertainty.

Uncertainty factors are used to address uncertainty. The NOAEL-to-LC50 method applies a total composite UF of 100 to 10th percentile of the cumulative percentage distribution of the NOAEL-to-LC50 ratios (a UF of 10 for animals to human extrapolation and a UF of 10 to account for human variability). In the TOC approach, the 10th percentile of the cumulative distribution of the NOAELs in each of five categories was determined and divided by an uncertainty factor of 100 (a UF of 10 for animals to human extrapolation and a UF of 10 to account for human variability). In some cases, only LOAELs were available and uncertainty factors of 10 or 6 were applied to calculate a NOAEL. Please refer to Grant et al. (2007) for a complete description of these methods.

G. Allow the calculation of risk (probability of response for the endpoint of interest) in the exposed human population?

Calculation of risk (probability of response) is not done. This methodology was originally developed to provide conservative screening values for regulated chemicals with limited toxicity data in the state of Texas. Regulated facilities and engineers reviewing the permits need clear, straightforward screening values, not distribution of risks.

H. Work practically? If the method still requires development, how close is it to practical implementation?

Since 2007, this method has been used to develop generic Tier II generic ESLs for the following chemicals with limited toxicity data: pentene isomers and hexane.

It has also been used to compare to ESLs based on multiple day studies for several chemicals. In all cases, the Tier II generic ESLs were more conservative or less than a factor of two higher when compared to the acute ESLs developed based on multiple day studies: 1,3-butadiene, 1-butene, 2-butene, isobutene, Texanol, toluene, tetrachloroethylene, ethylbenzene, and benzene.

As mentioned previously, if acute inhalation lethality studies are not available, then the Tier I - Threshold of Regulation Approach (default ESL) or Tier III - Relative Toxicity/Potency Approach (generic ESL) can be used.

References Cited:

Cramer, G.M., Ford, R.A., Hall, R.L. 1978. Estimation of toxic hazard—a decision tree approach. Food Cosmet. Toxicol. 16: 255–276.

Grant, R. L., Kadlubar, B. J., Erraguntla, N.K., and Honeycutt, M. 2007. Evaluation of acute inhalation toxicity for chemicals with limited toxicity information. Reg Tox Pharm 47: 261-73.

ten Berge, W.F., Zwart, A., Appelman, L.M. 1986. Concentration-time mortality response relationship of irritant and systemically acting vapours and gases. J. Hazard Mater. 13: 301–309.

Texas Commission on Environmental Quality. 2006. Guidelines to develop effects screening levels, reference values, and unit risk factors, RG-442. Texas Commission on Environmental Quality, available at

Texas Commission on Environmental Quality. 2008a. Development support document Pentenes CAS registry numbers: 1-pentene: 109-67-1, c-2-pentene: 627-20-3, t-2-pentene: 646-04-8. Texas Commission on Environmental Quality, Toxicology Section, Chief Engineer’s Office, available at

UN (United Nations). 2005. Globally harmonized system of classification and labeling of chemicals (GHS) First revised edition. ST/SG/AC.10/30/Rev.1 United Nations New York and Geneva.

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