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Epidemiological Concerns

The epidemiological evidence has played a disproportionately large role in the policymaking process. Time-series findings indicate associations of mortality with not only PM and ozone, but with all of the criteria pollutants. Because results of time-series studies implicate all of the criteria pollutants, findings of mortality time-series studies do not seem to allow one to confidently attribute observed effects specifically to individual pollutants. This raises concern about the utility of these types of studies in the NAAQS-setting process. Examples of inconsistenties and inconclusive findings include the following:

  • Instability of mortality effect estimates resulting from different model specifications of weather effects and time trends.
  • Instability of effect estimates resulting from different selections of monitoring sites within cities.
  • Increased heterogeneity of effect estimates across cities.
  • Greater diversity of findings among studies and across study areas.
  • Contradictory results from mortality displacement studies.
  • Effect lags that are inconsistent across cities and across studies.
  • Exposure-response relationships that are inconsistent across cities and across studies.
  • Inconsistencies between short-term and long-term effect studies, such as respiratory effects of fine particles.
  • Contradictory findings among long-term studies.

Smith et al. (2009) (Smith, Xu, and Switzer) discussed some of the concerns about the use of time-series data. The authors investigated intercity variability, as well as the sensitivity of the ozone-mortality associations to modeling assumptions and choice of daily ozone metric, based on reanalysis of NMMAPS data. Smith et al. (2009) examined the sensitivity of city-specific ozone-mortality estimates to adjustments for confounders and effect modifiers, showing substantial sensitivity. They examined ozone-mortality associations in different concentration ranges, finding a larger incremental effect in higher ranges, but also larger uncertainty. Alternative ozone exposure metrics defined by maximum 8-h averages or 1-h maxima show different ozone-mortality associations that the authors believed could not be explained by simple scaling relationships. The authors' view was that ozone-mortality associations, based on time-series epidemiologic analyses of daily data from multiple cities, revealed still-unexplained inconsistencies and showed sensitivity to modeling choices and data selection that contribute to serious uncertainties when epidemiological results are used to discern the nature and magnitude of possible ozone-mortality relationships or are applied to risk assessment.

Personal exposure is not reflected adequately, and sometimes not at all, by concentrations measured at central outdoor monitoring sites. Typically, personal exposures are much lower than the ambient concentrations, and can be dramatically lower depending on time-activity patterns, housing characteristics, and season. In addition, and of particular importance for the time-series studies, there can be no correlation between personal concentrations measured over time and concentrations measured at central outdoor sites.

Previous review comments made by our research group were associated with spatial variability and the statistical shortcomings associated with epidemiological analyses. Dr. Paul Switzer's comments on some of the shortcomings associated with the epidemiological findings can be read by clicking here. In a slide presentation, Dr. Lefohn, President of A.S.L. & Associates, summarized his group's findings on some of the concerns associated with the epidemiological methodology at an EPA Clean Air Scientific Advisory Committee (CASAC) meeting in North Carolina. Dr. Paul Switzer, a member of the technical team, provided written comments on his concerns about the shortcomings of the statistical methodology utilized in the time-series epidemiological analyses. His comments can be viewed by clicking here.

Professor Paul Switzer (Stanford University) and Dr. Allen S. Lefohn (A.S.L. & Associates) provided input to the EPA prior to the publication of the final version of the Carbon Monoxide Criteria Document (CD). A summary of our input is available in an Adobe Acrobat PDF file.

The growing pattern of inconsistent and inconclusive findings is troublesome and presents both scientists and policymakers with a very difficult decision. Simply stated, the science based on epidemiological results may not be substantial enough at the moment to provide the foundation upon which a clear path can be built that leads directly from the science to the policymaking decision arena.

It its 2013-2015 review by EPA of the national ambient ozone standard, the science based on epidemiological results did not provide strong support for reducing the current level of the Federal ozone standard in the US (FR Vol. 80, No. 206). In November 2015, the EPA Administrator concluded that the epidemiological risk analyses showed that small net benefits resulted from changing the ozone standard from its current level of 75 ppb to lower values (70, 65, or 60 ppb). EPA (2014) provided details supporting this observation by the Administrator. The Administrator's conclusion was based on the observation that because the short-term epidemiological risk analyses were integrated from the maximum concentration to zero concentration, minimum benefits occurred. As emission reduction occurred to meet lower proposed ozone standards, the lower concentrations began to rise (due to lack of NO scavenging) and the epidemiological models predicted that additional morality and morbidity might occur. Although benefits occurred as the higher ozone concentrations were reduced, this benefit was greatly neutralized by the rise in predicted mortality and morbitidy due to the low end of the concentration distribution rising. The result reported was associated with the model selected by the epidemiologists. The model apparently ignored the scientific observations reported (e.g., Hazucha and Lefohn, 2007; Lefohn et al., 2010) that higher ozone concentrations should be provided greater weight than lower concentrations of which many of the lower values are in the background range (i.e., 25-55 ppb) (see Lefohn et al., 2014). The large frequency of lower concentrations results in the lower concentrations contributing an inappopriate weighting when benefits are calculated. Additional discussion of the lack of NO scavenging affecting the movement of the lower hourly average ozone concentrations toward the mid-levels can be found in Lefohn et al. (2017) and Lefohn et al. (2018). As noted above, the observation that benefits were greatly neutralized by the rise in predicted mortality and morbitidy due to lower concentrations that were rising is an artifact of the epidemiological modeling. The EPA in the 2013-2015 ozone rulemaking cycle attempted to deal with this problem by artificially applying a "threshold" to diminish the contribution of the lower concentrations.

In the October 2015 national ambient ozone standard decision, the EPA Administrator noted that she placed the greatest weight on controlled human exposure studies, citing significant uncertainties with epidemiologic studies. Reasons for placing less weight on epidemiologic-based risk estimates were key uncertainties about (1) which co-pollutants were responsible for health effects observed, (2) the heterogeneity in effect estimates between locations, (3) the potential for exposure measurement errors, and (4) uncertainty in the interpretation of the shape of concentration-response functions for ozone concentrations in the lower portions of ambient distributions.

As EPA initiates a review of the Agency's December 2020 decision to retain the 2015 ozone human health and vegetation standards, CASAC and the Agency will have to deal with the uncertainties associated with integrating epidemiological results into the standard-setting process. Uncertainties noted by the EPA in its 2015 decision:

(1) which co-pollutants were responsible for health effects observed,
(2) the heterogeneity in effect estimates between locations,
(3) the potential for exposure measurement errors, and
(4) uncertainty in the interpretation of the shape of concentration-response functions for ozone concentrations in the lower portions of ambient distributions.

will again have to be revisted.


Federal Register. Vol. 80, No. 206 / Monday, October 26, 2015. National Ambient Air Quality Standards for Ozone, 40 CFR Part 50, 51, 52, 53, and 58, pp 65292-65468.

Hazucha, M. J.; Lefohn, A. S. (2007) Nonlinearity in Human Health Response to Ozone: Experimental Laboratory Considerations. Atmospheric Environment. 41:4559-4570.

Lefohn, A.S., Hazucha, M.J., Shadwick, D., Adams, W.C. (2010). An Alternative Form and Level of the Human Health Ozone Standard. Inhalation Toxicology. 22: 999-1011.

Lefohn, A.S., Emery, C., Shadwick, D., Wernli, H., Jung, J., Oltmans, S.J. (2014). Estimates of Background Surface Ozone Concentrations in the United States Based on Model-Derived Source Apportionment. Atmospheric Environment, 84: 275-288.

Lefohn, A.S., Malley, C.S., Simon, H., Wells. B., Xu, X., Zhang, L., Wang, T., 2017. Responses of human health and vegetation exposure metrics to changes in ozone concentration distributions in the European Union, United States, and China. Atmospheric Environment 152: 123-145. doi:10.1016/j.atmosenv.2016.12.025.

Lefohn, A.S., Malley, C.S., Smith, L., Wells, B., Hazucha, M., Simon, H., Naik, V., Mills, G., Schultz, M.G., Paoletti, E., De Marco, A., Xu, X., Zhang, L., Wang, T., Neufeld, H.S., Musselman, R.C., Tarasick, T., Brauer, M., Feng, Z., Tang, T., Kobayashi, K., Sicard, P., Solberg, S., Gerosa. G. 2018. Tropospheric ozone assessment report: global ozone metrics for climate change, human health, and crop/ecosystem research. Elem Sci Anth. 2018;6(1):28. DOI:

Smith, R.L., Xu, B., and Switzer, P. (2009). Reassessing the relationship between ozone and short-term mortality in U.S. urban communities. Inhalation Toxicology, 29(S2): 37–61.

US Environmental Protection Agency, US EPA. (2014). Health Risk and Exposure Assessment for Ozone. EPA/452/R-14-004a. Research Triangle Park, NC: Office of Air Quality Planning and Standards. August.

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