Document ID: EPA-HQ-OPPT-2012-0018-0470
Agency: epa
Document Type: Supporting & Related Material
Title: 
Posted Date: 2013-06-10T04:00Z

EPA Response to Peer Review Comments
                                       
                                       
                External Peer Review of EPA's Draft Document
Approach to Assessing Non-cancer Health Effects from Formaldehyde and Benefits from Reducing Non-cancer Health Effects as a Results of Implementing Formaldehyde Emission Limits for Composite Wood Products
                                       
                                       
                                       
                                       
                                       
                                       
                                Peer Reviewers:
                                       
                             John R. Balmes, M.D.
                           Glenn C. Blomquist, Ph.D.
                         A. Myrick Freeman III, Ph.D.
                             Shelby Gerking, Ph.D.
                             David Kriebel, Sc.D.
                    Frederick J. Miller, Ph.D., Fellow ATS
                         Rebecca T. Parkin, Ph.D., MPH
                                       
                                       
                                       
                                       

                            I.  GENERAL IMPRESSIONS
                                     NAME
                                    COMMENT
                                   RESPONSE
John R. Balmes, M.D. 
The document is clearly and concisely written.  The background subsections of Section 2: Non-cancer Health Effects  -  Derivation of Concentration-Response Functions for sensory irritation (2.1.1), asthma (2.2.1), and female reproductive toxicity (2.3.1) are extremely brief, especially the latter two.  While it is understandable that the EPA does not wish to be duplicative of the material in the draft IRIS document on formaldehyde or the NAS review of the IRIS document, some readers of the "Approach" document will not have read the IRIS and NAS documents and thus will benefit from a bit more background context on formaldehyde and asthma or formaldehyde and female reproductive toxicity.
The aim of Section 2 is to present the development of the concentration-response functions, so details of the health effects themselves are deliberately brief.  More detailed information can be found in the draft IRIS assessment.
David Kriebel, Sc.D.
The overall impression is of a thoughtful and well-written document. The authors have provided a generally clear and logical explanation of their reasoning throughout. There are a few exceptions, noted below, where additional explanation or documentation could improve the presentation.
No response required.
Frederick J. Miller, Ph.D., Fellow ATS
The comments provided are related to the health assessment and concentration-response evaluation portion of the above cited document as this reviewer was not asked to comment on the economic benefits assessment approach. For the most part, the sections on sensory irritation, asthma, and female reproductive toxicity are clearly presented and the material is developed in a logical manner. Some exceptions are noted in this reviewer's responses to the specific charge questions. The decision on the concentration-response functions to take forward to the economic benefits analyses is best documented for sensory irritation. This reviewer provides a suggestion for how far below 100 ppb of formaldehyde the modeling results developed by the Agency based on the Hanrahan et al. (1984) study can be used. The material included in support of using the McGwin et al. (2010) meta analysis for asthma in children does not adequately describe the short comings of the meta analysis. The uncertainties and conflicting results of the studies make this reviewer reticent to endorse the concentration-response function for the odds ratio based on the McGwin et al. (2010) meta analysis. The case to use background adjusted exposure data for the female reproductive toxicity concentration-response curve is adequately defended. However, the Agency does not indicate if the linear risk or the exponential risk curve will be used.

Overall, the information presented is accurate. To their credit, in a number of places, the EPA authors have incorporated criticisms included in the NAS report of the Agency's draft IRIS assessment document. By addressing the responses to the charge questions, the Agency will be in a good position to move forward with the cost benefit analysis required by Executive Order 12866 related to the Formaldehyde Standards for Composite Wood Products Act. 
No response required.  (Specific issues addressed in comments below).
Rebecca T. Parkin, Ph.D., MPH
The draft is clearly organized and, in large part, well-written.  Minor inaccuracies are noted below.  Most sections were clear, although some key issues were not mentioned or are not clear; these concerns are noted below.  Except in a few instances as noted below, the conclusions are effectively supported by the text provided.

Uncertainties are important to discuss.  EPA has captured many of the important ones, but may need to add more to these sections based on this and other reviewers' comments.  Being thorough in all uncertainty sections is crucial to the foundations of the benefit assessments.
EPA has added further discussion of uncertainties addressing reviewer comments.
II.  RESPONSE TO CHARGE QUESTIONS
CHARGE QUESTION 1: The literature base of residential epidemiology studies of the irritation effects with quantitative concentration-response data was limited, but data were available from which a concentration-response function could be estimated for eye irritation.

Please comment on whether the concentration-response function is appropriately derived from the studies used in the draft Approach Document.
                                     NAME
                                    COMMENT
RESPONSE
John R. Balmes, M.D. 
The concentration-response function (CRF) for sensory irritation is derived from one small field study, Hanrahan et al. (1984).  Because most individuals exposed to formaldehyde from the products of interest will be exposed at levels below 100 ppb, the EPA is appropriately concerned about the form of the CRF in this range.  Unfortunately, the data for exposures below 100 ppb are not given in the original Hanrahan paper and the regression of prevalence of eye irritation and formaldehyde concentration in the paper covers the range of 100-800 ppb.  Another issue regarding CRF derivation from the Hanrahan paper is the relatively small sample size (n=61).  The Liu et al. (1991) study, which involved a much larger population, is supportive of the concept that there is a CRF for formaldehyde and eye irritation at relatively low levels of exposure, but was not used in the actual derivation of such a CRF because of the way the authors aggregated their data into low, medium, and high levels of exposure.
The regression covers the whole range of exposures ("< 0.10 ppm to 0.80 ppm"); however, in Hanrahan et al.'s Figure 1, only modeled prevalences for exposures >= 100 ppb are portrayed.  The Hanrahan et al. study is relatively small; however, as noted by the reviewer, the Liu et al. study is supportive.
David Kriebel, Sc.D.
I see no problems with the derivation of the concentration-response function itself. In Section 2.1.3, I think it would strengthen the argument to at least acknowledge the problem of acclimatization. There is evidence from a number of studies  -  notably the studies of studies conducting autopsies  -  that there is a change over weeks in the short-term irritant effects. One way that this will impact the calculations is that cumulative exposure is probably not the appropriate exposure metric. The authors may have little choice to use the simplified approach they have taken which assumes a constant exposure-response relationship over time, but they could acknowledge that there is a source of uncertainty from the changes in potency of formaldehyde over time for various endpoints. I suspect that the irritant effects diminish with time exposed, but the other two chosen endpoints probably do not.
EPA has added some discussion of acclimatization.
Frederick J. Miller, Ph.D., Fellow ATS
The draft Approach Document adequately discussed the type of data available in the literature from various studies and presented their strengths and weaknesses. The Agency wisely stayed away from using the Liu et al. (1991) study as the primary driver for the concentration-response function for eye irritation. The categories from that study were formed on using a ppm-hr per week metric. The eye irritation studies discussed in Section 2.1.2 for a 10 % additional risk for 560 ppb for 3 hours (i.e., 1,680 ppm-hrs) compared to 240 ppb for 5 hours (i.e., 1,200 ppm-hrs) clearly show that Haber's Law does not apply for the effects of formaldehyde exposure on eye irritation, which agrees with Miller et al. (Haber's rule: a special case in a family of curves relating concentration and duration of exposure to a fixed level of response for a given endpoint. Toxicology 149:21 - 34, 2000). Thus, the Agency would have been hard pressed to defend a translation of the ppm-hrs metric of Liu et al. (1991) as the basis for developing a concentration-response function for eye irritation.

Rather, the Hanrahan et al. (1984) study that reported eye irritation was associated with in-home formaldehyde exposures (p < 0.05) (both as "burning eyes" and "eye irritation") was used as the data for developing a concentration-response relationship for eye irritation. Moreover, the logistic regression model developed by Hanrahan et al. (1984) gave insight as to the needed nature of the curve if one were to extrapolate below the range of exposures reported by those authors (i.e., from 100 to 800 ppb). In the opinion of this reviewer, the concentration-response function was appropriately derived by the Agency.

No response required.
Rebecca T. Parkin, Ph.D., MPH
First, I will comment on each study and then on the derivation process.

Liu et al (1991): This paper adequately describes how homes were randomly selected, but omits some key information related to monitoring results for the homes included.  The study was conducted throughout California (p. 93); a very large state with a wide range of climatic conditions.  "Summer" and "winter" sampling periods were used, but these seasons are quite different in different parts of the state.  It is well-known that temperature and relative humidity affect formaldehyde (HCHO) levels, but there is no mention of how these factors varied in the study homes or how they may have affected measured HCHO levels.  Further, the Quality Assurance/Quality Control methods are not described, and the number of laboratories used to analyze the passive area monitoring samples is not stated.  These omissions leave this reviewer without key information to assess the accuracy or validity of the HCHO levels reported.  

Residents received instructions on how to uncap, place and mail back the samplers.  The use of the kitchen and master bedroom as monitoring sites may be most relevant for the homeowner and less relevant for other occupants.  Although averaging the monitored levels for each home may have lost some useful variation, it is not likely that in fairly small homes (such as mobile homes) that this loss  -  except for peak exposures  -  would be particularly important.  

The study appropriately controls the impact of smoking indoors, and does not discuss gas cooking stoves or appliances, opening of windows and doors, or other factors that have been reported by other authors as having non-significant impacts on HCHO levels.  

More importantly, if I am reading the article correctly (p. 92), some indoor samples in this cross-sectional study were taken after symptoms were recorded.  This conflicts with determining the appropriate temporal sequence of cause preceding effect.  I believe my reading is different from what EPA states on p. 10 of their draft, which indicates that exposures were recorded in a period preceding the documentation of symptoms.

Hanrahan et al (1984):  This cross-sectional study, conducted in Wisconsin during July 1979, sampled a smaller number of mobile homes (65) than did Liu et al.; it also had a lower percentage of participants among those contacted (31% vs. 44%).  In this study, personal samplers were used and 33 outdoor samples were taken (at least 1 in each mobile home park).  The authors noted that prior to and during sampling periods home windows were closed, gas appliances were turned off and smoking was prohibited.  

The Quality Control and specific laboratory methods were noted (unlike in Liu et al).  The indoor samples for each home were averaged, as in Liu et al, with similar but less specific sampling locations noted.  It is not clear whether the residents or the researchers collected the air samples in this study.  

Smoking was appropriately considered, and indoor and outdoor temperature and humidity, and appliance and construction characteristics were noted.  Some but not all of these factors' influences on HCHO levels were presented in the article.

Derivation:  The seasonal and cumulative averages and ranges of indoor levels, the concentration-response data are correctly extracted from the Liu et al. article.  The method to estimate the average number of hours indoors seems appropriate; however, this reviewer wonders whether EPA attempted to determine whether the authors still have the raw data that could be used for a more accurate assessment of hours spent indoors.

EPA had to make many more adjustments when using the Hanrahan et al. article.  First, EPA estimated the lower bound for the indoor levels based on the standard deviation for the outdoor levels; this is a reasonable approach given the missing data for the indoor levels.  Second, the Agency assumed that the distribution of indoor levels is log-normal in order to estimate the number of samples with HCHO levels below 100 and 50 ppb.  However, if this assumption or the estimated standard deviation is not correct, the numbers of samples could be quite different.  

It is not clear in Figure 2 whether the data shown are for EPA's or the authors' use of "eye irritation;" e.g., does "eye irritation" here mean the "burning eyes" AND "eye irritation" results in the article?  If combined data were used, did EPA assume that all of these symptoms were distinct and not co-occurring events?  Are we looking at data for the number of symptoms reported or the number of people with eye symptoms (meaning "burning eyes" and "eye irritation") at each level of exposure?  This question should also be asked of the data shown in the draft Table 1.  Without knowing whether EPA combined data in Figure 2 and Table 1, it is difficult to comment further on this part of the draft.

The conversion of data in the article to prevalence odds seems appropriate.  The display of estimates below 150 ppb in Figure 4b are derived from Equation 2-2 and are likely correct.   This reviewer did not verify the mathematics.

The EPA authors have noted many key uncertainties in the two studies and how these affect their estimates of the relational function.  However, the validity of the HCHO monitored levels remains a question, due to missing information in the articles; exposure misclassification is possible in both studies but is not discussed in the draft.  

EPA has corrected this.

No, EPA used solely what was presented in the paper.

EPA has added additional discussion about the distributional assumption.

EPA has clarified that the results in Fig. 2 are for "burning eyes" only but that EPA is using this endpoint to represent eye irritation more broadly.

EPA has added more discussion about the uncertainties associated with exposure sampling in these studies.
CHARGE QUESTION 2: Please comment on the validity of extrapolating the concentration-response function and using the function to estimate effects at concentrations below 100 ppb.
                                     NAME
                                    COMMENT
RESPONSE
John R. Balmes, M.D. 
Given the limitations of the data available from the Hanrahan paper, the method of derivation of the CRF including the portion of the curve below 100 ppb is appropriate, but the extrapolation is pushing the envelope of what reasonably can be extracted from the data.  The assumption that the reported standard deviation of the outdoor formaldehyde measurements represents the lower bound on the standard deviation of the indoor concentrations appears reasonable, but nonetheless the distribution of exposure data below 100 ppb in the Hanrahan study was assumed rather than based on the actual data.  The EPA used the graphical display of the regression data over the range of 100-800 ppb in the Hanrahan paper to derive a CRF and then to infer the shape of the CRF below 100 ppb.  Given that the Hanrahan study only included 61 subjects and that the formaldehyde measurements in the mobile homes were only for 30-60 minutes, the validity of the extrapolated CRF can be questioned even if an appropriate method was used.
EPA has added some discussion of the short-term sampling used by Hanrahan et al. to the uncertainties section (Section 2.1.4).  EPA notes that the Liu et al. study, which used 7-day sampling is supportive of the Hanrahan et al. results
David Kriebel, Sc.D.
I am comfortable with this extrapolation. However, I think that it would be appropriate to acknowledge that errors in exposure estimation in the studies on which the function is based have not been included in the uncertainty calculations. This is a general concern  -  for all 3 endpoints, there were certainly errors in the exposure estimation, and the impact of these on the uncertainty in the exposure-response function has not been considered.

It might be noted that the extrapolation downwards assumes a logistic shape, which is reasonable but not subject to validation. It might be noted that the excellent R[2] for Figure 3b is a bit misleading since it is fitting a curve to categorical data, while the actual individual exposure data were of course continuous  -  the fit of this curve to the original data would not have been nearly as good. And again, see my comment just above about failure to point out that the exposure data had error, which was not taken into consideration in the model error calculations.
EPA has added discussion of exposure measurement error.

EPA has clarified that the point of the R[2] value was to compare EPA's attempt to recreate Hanrahan et al.'s model to the discrete model predictions (not categorical data) presented by Hanrahan et al.
Frederick J. Miller, Ph.D., Fellow ATS
The Agency appropriately focused on the data from the Hanrahan et al. (1984) study to develop the concentration-response curve for eye irritation. Importantly, the Agency used a power law curve to fit the prevalence odds data. This ensures that the fitted curve will asymptotically approach zero for a zero formaldehyde exposure level and makes it reasonable to use Equation 2.2 below 100 ppb. Given (1) the limit of detection (LOD) was 10 ppb at the time the Hanrahan et al. (1984) study was conducted, (2) the Agency's assumption about the outdoor standard deviation of measurements being 30 ppb around a log-normal distribution of measurements, and (3) the known overall shape of the concentration-response curve below 100 ppb, this reviewer believes it would be reasonable for the Agency to use the fitted equation down to a level of about 40 ppb, which would correspond to the LOD plus one standard deviation.
Given the general support from the other reviewers, the absence of alternative response estimates for residential exposures below 40 ppb, and the difficulties in rationalizing a cut-off based on an unreported LOD and an estimate for the SD that was presented for illustrative purposes only, EPA has decided against using 40 ppb as a cut-off for the model below 100 ppb.
Rebecca T. Parkin, Ph.D., MPH
The validity of the extrapolation in the Hanrahan et al. paper depends in part on what data were used for the outcome measure.  If "burning eye" AND "eye irritation" data were combined, more information is needed in the draft to describe what assumptions were made in the combining process.  (See comments above.)

The validity of the estimates below 100 ppb based on the Hanrahan et al. data is strengthened by their alignment with the results in the Liu et al. study.

However, clearer discussion of the Agency's choice of and uncertainties in the points of departure would improve this portion of the draft. 
EPA has clarified that only "burning eyes" was modeled.

EPA has added discussion about uncertainties in the data and in the derivation of the exposure-response relationship.  For the purposes of this document, the exposure-response relationships are used to estimate risks at exposure levels of interest.  This methodology does not involve points of departure.
CHARGE QUESTION 3: The studies considered for the concentration-response function are residential studies because residential exposures are the focus of the rule and the residential studies avoid some of the limitations of other types of studies (e.g., controlled exposure chamber studies used high, acute exposures, and occupational studies reflect high exposure levels and potential dose-rate effects from peak exposures).  Are there other studies (e.g., chamber or non-residential studies) that should be used as supporting evidence for the currently derived concentration-response function for eye irritation?  If so, please provide information about the studies and discuss how they should be used to support the concentration-response function.
                                     NAME
                                    COMMENT
RESPONSE
John R. Balmes, M.D. 
I do not know of other studies that would be better to use for derivation of a CRF for formaldehyde exposure and sensory irritation given the EPA's interest in chronic, low-level, non-peak exposures.
No response required.
David Kriebel, Sc.D.
I think you should use the other studies  -  particularly the chamber studies and the autopsy studies  -  to show the consistency of the findings across many settings. I am comfortable with the argument that the function should be derived from the residential studies. But I think that the logic of extrapolating downwards is supported by some of the other studies. Kriebel et al. Arch Env Hlth 2001; 56:11- 18 contains fairly detailed exposure data linked to eye irritation scores. While much of the data are above the range you are concerned with, there is evidence here that the relationship observed was valid across the full range of exposures.
EPA has added some discussion of non-residential studies and has cited the Kriebel et al. (2001) study.
Frederick J. Miller, Ph.D., Fellow ATS
Beyond the studies considered by EPA, this reviewer knows of no chamber or epidemiology studies that would be useful in developing the concentration-response function for eye irritation. Given the definition of an inhalation RfC and the focus on extended periods of exposure, the residential studies were conducted in a manner that best fits the criteria for developing a RfC and using it in the benefits analyses that the Agency is being required to conduct.
No response required.
Rebecca T. Parkin, Ph.D., MPH
I am not aware of any other studies that should be considered for this function.
No response required.
CHARGE QUESTION 4:  Are there other sensory irritation endpoints besides eye irritation for which a concentration-response function can and should be developed for assessing effects at concentrations below 100 ppb?  If so, please provide references of appropriate studies and a description of how the studies could be used to develop a concentration-response function.
                                     NAME
                                    COMMENT
RESPONSE
John R. Balmes, M.D. 
I do not know whether a CRF can be developed for other sensory irritation endpoints. 
No response required.
David Kriebel, Sc.D.
Both nose and throat irritation can be linked to increased risk of lower respiratory tract infection including bronchitis. So you could argue that these would have greater economic impacts. 
Without data linking the effects or linking formaldehyde exposure directly to RTIs, EPA cannot develop exposure-response functions for those effects.  In addition, there are other effects for which EPA has hazard data but for which exposure-response functions could not be derived and, hence, for which no benefits could be calculated.
Frederick J. Miller, Ph.D., Fellow ATS
Sensory irritation may be indirectly reflected in pulmonary function responses measured after exposure to formaldehyde. However, these studies were not conducted at levels that would be relevant to what the Agency is being charged with investigating.
There are studies linking formaldehyde exposure directly to decreased pulmonary function (e.g., Krzyzanowski et al., 1985); however this effect could not be linked to specific economic costs and, hence, was not included in the Approach document.  EPA has added text to this effect in the introduction.
Rebecca T. Parkin, Ph.D., MPH
I agree with EPA and NAS that eye irritation is the most sensitive sensory irritation endpoint and therefore is the most appropriate endpoint to use. 
No response required.
CHARGE QUESTION 5:  Several studies of the association between formaldehyde and asthma have been published and these were quantitatively summarized in a meta-analysis by McGwin et al. (2010).

Please comment on whether the McGwin et al. (2010) meta-analysis is an appropriate summary of the association between formaldehyde inhalation exposures and childhood asthma.
                                     NAME
                                    COMMENT
RESPONSE
John R. Balmes, M.D. 
The McGwin et al. (2010) meta-analysis of the association between formaldehyde exposure and risk of asthma in childhood appears to have been well conducted, using state-of-the-art methods, including both fixed and random effects models and various sensitivity analyses.  Because the meta-analysis was based on a systematic review of the literature that appears to have been comprehensive, the results can be considered an appropriate summary of what is known about the association from epidemiological studies.
No response required.
David Kriebel, Sc.D.
I agree that it is appropriate.
No response required.
Frederick J. Miller, Ph.D., Fellow ATS
There are many problems with the studies used in the meta analysis conducted by McGwin et al. (2010). Relative to the description of the metal analysis, the Agency did a reasonable job of pointing out many of the strengths and weakness that McGwin and colleagues noted in their paper, but this description could be improved. 

There are various inconsistencies in the studies selected for the meta analysis that would make this reviewer reticent to put much trust in the findings for applicability to the U.S. population. First, only one study was conducted in the U. S. and that study did not find a statistically significant odds ratio (OR) with exposures being in the range of 30 to 80 ug/m[3] of formaldehyde. Moreover, the sample size of the U.S. study was greater than that of 5 of the other studies contained in Table 1 of McGwin et al. (2010).

A Swedish study with exposures no greater than 10 ug/m[3] had an OR more than twice that of any other study even though several of those studies involved formaldehyde exposures in the 5 to 70 ug/m[3] range, including another Swedish study. The Zhao et al. (2008) study results are inconceivable to this reviewer for inclusion in a reliable meta analysis. With school exposures (1 to 5 ug/m[3]) and outdoor exposures (5 to 7 ug/m[3]), mean OR estimates were found to represent decreased risk, yet the upper bound of the 95 % confidence interval was 17 for the school OR and more than 2.3 million for the outdoor OR for the same set of 1,993 children having a mean age of 12.8 years. 

McGowan et al. (2010) state that to evaluate whether the results they found were unduly influenced by any individual study and to determine if there was any publication bias, an influence plot and a funnel plot, respectively were used. However, they did not present these plots in their paper. The computed values of the Q and I[2] statistics were stated to support the presence of moderate between-study heterogeneity. The EPA document cites values for these statistics but does not explain how they are calculated, but should do so. Q (better known as Cochran's Q) is a classical measure of heterogeneity and is calculated as the weighted sum of squared differences between individual study effects and the pooled effect across studies, with the weights being those used in the pooling method. Q is distributed as a chi-square statistic with k (number of studies) minus 1 degrees of freedom (d.f.). The I[2] statistic describes the percentage of variation across studies that is due to heterogeneity rather than chance and is computed as 100* (Q  -  d.f.)/Q.

On page 18 of the EPA document, the overall OR for a fixed effects model is given as 1.026 but on page 20 the same result is stated as an OR of 1.03. The Agency needs to be consistent. If the data are only sufficient to give an OR with 2 digits after the decimal point, say so and change the value on page 18 and vice versa. For the reader to better judge the reasonableness of the meta analysis results, the EPA document should include Table 1 of the McGwin et al. (2010) paper in addition to Figure 1 from that paper.
EPA notes that other reviewers stated that the meta-analysis was appropriately conducted.

The meta-analysis was based on available studies of which most were conducted outside the U.S.

Inclusion criteria were not conditional upon the findings.  
EPA has clarified that the confidence intervals for the Zhao et al. study are so large that the study has virtually no weight in the meta-analysis; thus, its inclusion is inconsequential.

EPA has added descriptions of the Q and I[2] statistics.

EPA has addressed this discrepancy in reporting of decimal places.
EPA has added McGwin et al.'s Table 1.
Rebecca T. Parkin, Ph.D., MPH
The authors clearly built on well-accepted guidelines for systematic meta-analysis (Stroup et al., 2000).  The study selection/exclusion criteria and process used by McGwin et al. is well-documented in their article.  The variables extracted and utilized are stated.  The determination to use a consistent metric (odds ratio per 10 ug/m[3] with the related 95% confidence interval) across the 7 studies for which actual HCHO measurements were available is appropriate.  The methods used to pool the odds ratios and test for heterogeneity are standard analytic approaches.  Their evaluation of the potentially undue influence of any one study, using influence and funnel plots, adds strength to their analysis.  The results are shown with and without Rumchev et al., allowing the reader to judge whether this paper should have been included or not.  The data in Table 2 indicate that the magnitude of the HCHO effect on asthma prevalence is significant whether this study is included or not.  The presentation of the Q and I[2] statistics guides the reader to the key results for interpreting the data in this table.  In summary, this reviewer finds that the McGwin et al. meta-analysis is an appropriate summary and synthesis of the eligible studies reporting a quantitative relationship between HCHO and prevalence of childhood asthma.
No response required.
CHARGE QUESTION 6: Please comment on whether EPA chose the appropriate function from the McGwin et al. paper to use in the benefits assessment.
                                     NAME
                                    COMMENT
RESPONSE
John R. Balmes, M.D. 
Exponentiating the linear slope of the fixed effects model from the McGwin et al. paper is appropriate, especially given that the random effects model gave essentially the same pooled odds ratio.
No response required.
David Kriebel, Sc.D.
I am comfortable with the choice to exclude Rumchev, and agree with the derivation of the function as described.
No response required.
Frederick J. Miller, Ph.D., Fellow ATS
The EPA document does not specifically state which model result (i.e. fixed effects or random effects) was selected. Rather they state that the mean OR was 1.24 per 10 ug formaldehyde per m[3] for both models. One only determines that the Agency chose to use the random effects model if one calculates the transformed 95 % confidence interval for an OR for an increase of 1 ppb and sees that what is stated on page 18 corresponds to the confidence interval for the random effects model. 

The lack of significant between-study heterogeneity in the meta analysis of McGwin et al. (2010) supports using a fixed effects model; however, the extent of the uncertainties among the studies and the fact that the random effects confidence interval will always be larger than the fixed effects confidence interval supports the conservative selection by the Agency to use the random effects model results.

In view of the additional problems this reviewer discussed earlier concerning the choice of studies for inclusion in the meta analysis, this reviewer would be reticent to have the benefits assessment use only one function (i.e., the OR of 1.03 per one ppb increase in formaldehyde exposure with a 95 % confidence interval from 1.008 to 1.047). The single U.S. study should also be evaluated wherein the OR is 1.0083 per 1 ppb increase in formaldehyde exposure with a 95 % confidence interval of 0.97 to 1.045.  
EPA has clarified that it selected the random-effects model and has provided a rationale for this selection.

The single U.S. study did not adjust for other factors while the remainder of studies did, and EPA considered the identified meta-analytic result to be more robust that that of a single study.
Rebecca T. Parkin, Ph.D., MPH
The Agency has chosen the appropriate function from the McGwin et al. paper.  With the exception of the discussion of the rationale for excluding Rumchev et al., however, more insightful comments about the strengths of the meta-analysis would lend greater support to the Agency's use of and reliance on the fixed-effects model's OR=1.24.  Deepening the discussion would improve the support for the Agency's conclusions and recommendation.  For example, McGwin et al. stated that an I[2] value of <50% would point to relying on the fixed-effect results (p. 314).  Although the Agency uses the fixed-effect modeling results, correctly stating that the Q and I[2] data indicate low heterogeneity, the draft does not include the key cut-point (I[2]<50%) for the use of fixed- vs. random-effect modeling results.   In this reviewer's opinion, pointing the reader explicitly to this cut-point and the relevant data in McGwin et al.'s Table 2 would sharpen the Agency's rationale for choosing the fixed-effect results

The discussion of uncertainties in this section includes the key issues (such as the changes in definition and determination of "asthma" over time) and is appropriately written.
EPA has clarified that it selected the random-effects model and has provided a rationale for this selection
CHARGE QUESTION 7: The literature base describing reproductive effects of formaldehyde exposure in humans is limited; however, there are supportive findings from the animal toxicological literature.  The epidemiologic literature suggests an association between formaldehyde and increased risk of spontaneous abortion and a related delay in time to pregnancy (i.e., reduced fertility).  The only study with quantitative concentration-response data was Taskinen et al. (1999).

The a priori hypothesis in Taskinen et al. (1999) was that formaldehyde would be associated with decreased fertility.  The primary analyses showed that there was a statistically significant reduction of fertility among the women in the highest exposure group that appeared to be concentration dependent.  Post-hoc subgroup analyses showed that stratification of the 39 women in the highest exposure group by reported glove use yielded effect estimates whose confidence intervals overlapped.  The FDR for the 17 women who were classified as not wearing gloves was 0.51 [95% CI: 0.28−0.92].  The FDR for women who were classified as always or sometimes wearing gloves was 0.79 [95% CI: 0.47−1.23].  
   
In light of the results regarding glove use, in what way(s) can the Taskinen et al. results be used to support calculating a concentration response for formaldehyde inhalation risk to time to pregnancy?
                                     NAME
                                    COMMENT
RESPONSE
John R. Balmes, M.D. 
The results of the stratified analysis regarding glove use are suggestive of the possibility that the dermal route may contribute to total exposure, but are not adequate to consider modification of a CRF for decreased fertility based on inhalational exposures, especially given the small size of the two strata and the wide confidence intervals of the FDR point estimates.
No response required.
David Kriebel, Sc.D.
Yes, but you could strengthen your argument. First, there is a trend in both FDR and spontaneous abortion across levels of formaldehyde, so you should not only focus on the effect modification by glove use in the high exposure group. While the high exposure is the only group for which the authors provided the results stratified by glove use, the fact that there is a trend across air concentrations suggests that glove use  -  not constant across exposure levels  -  could not be a very important source of protection or you would not see the trend. Second, you have not correctly dealt with the question of whether or not there is effect modification by glove use. The overlap of confidence intervals is not the correct way to do this. Construct the null hypothesis that glove users and non-users have the same FDR and then calculate a p-value testing this null. You can do it with the data provided  -  back calculate the standard errors from the confidence intervals, or ask the authors for the standard errors. I am pretty sure that this p-value will be large, and then you will be in a strong position to say that the appropriate conclusion is to act as if glove use has not modified the FDR. 
A p-value calculation has been added.
Frederick J. Miller, Ph.D., Fellow ATS
The results after stratifying for glove use are indirectly supportive for an inhalation effect of formaldehyde on the fecundity density ratio (FDR). Those women who did not wear gloves had a statistically significantly decreased FDR of 0.51 (i.e., 95 % confidence interval did not include 1). Women classified as always or sometimes wearing gloves had a FDR closer to 1 and their confidence interval included 1. Thus, the inclusion of women wearing gloves would tend to move the overall FDR closer to 1, where FDR values lower than 1 can be interpreted as an adverse effect in that the time to achieve conception is delayed. This was indeed the case since a FDR of 0.64 was found for all women in the highest exposure group. This provides evidence in support of the hypothesis that effects on FDR were most likely due to inhalation exposure rather than to dermal exposure to formaldehyde.
No response required.
Rebecca T. Parkin, Ph.D., MPH
The article (p. 208) is not clear as to whether the post-hoc analysis was adjusted for the variables noted in the footnote of Table VI; if not, the post-hoc results would not be directly comparable to the data presented there.  That said, the reported post-hoc high exposure group glove/not odds ratios and confidence intervals expand and are consistent with the trend shown in Table VI.  However, all of the confidence intervals overlap each other, yielding a set of non-significant odds ratios.  If the adjusted post-hoc odds ratios are available, it would be interesting to see the results of a test for trends comparing high exposure-gloves not used, high exposure-gloves used, medium exposure, and low exposure.  The trend probably is not significant, but testing its significance may offer more information for interpreting the concentration-response relationship.
EPA has included a test for heterogeneity across the strata of reported glove use in the highest exposure group, which yielded the result that the ORs for the glove-use subgroups are not significantly different
CHARGE QUESTION 8: Please comment on whether the concentration-response function is appropriately derived from the Taskinen et al. (1999) study.
                                     NAME
                                    COMMENT
RESPONSE
John R. Balmes, M.D. 
The CRF for formaldehyde exposure and decreased fertility appears to be appropriately derived from the Taskinen et al. (1999) study.  The adjustment for probable exposure to formaldehyde outside of the workplace is appropriate given the interest of the EPA in potentially controlling indoor exposures due to off-gassing from certain products.  The use of reasonably contemporaneous background exposure data from Finland (Jurvelin et al., 2001) for this adjustment is also appropriate.
No response required.
David Kriebel, Sc.D.
Can't you ask Taskinen to confirm your (and my) assumption that age was the conditioning time variable in their FDR calculations?

The process of adjusting for background exposure is OK, but I don't think it strengthens the presentation. First, I doubt very much that the relevant background formaldehyde exposure for the women in this plant could have been so much higher than the levels inside the plant. My guess is that the mean (one mean for an entire country over a long period of time? How useful is that?) had a wide range around it. Second, any of my graduate students could have told you that adding a constant to all the x values in a regression model will not change the slope.
EPA did not receive a response from the author.  As noted, the standard practice is to condition on age.

EPA has clarified the discussion of the adjustment for "non-work-station" exposure, which apparently was mis-understood by this reviewer.
Frederick J. Miller, Ph.D., Fellow ATS
A concentration-response function can be derived from the Taskinen et al. (1999) study, and the selected function must be one for which there was an adjustment for background exposure levels; however, the EPA document does not actually state whether they will use the linear function of risk or the exponential function of risk equations that are discussed in the document (i.e. will the Agency use Eq. 2-5 or 2-6?).

The two curves presented in Figures 6 and 7 of the Agency document are not explained either in the figure legend or in the text. While they obviously relate to the regression of risk on formaldehyde concentration, their difference is not explained. The Agency clearly picked up on most of the criticisms provided by the NAS review of the draft IRIS document related to the Taskinen et al. (1999) study. However, the Agency's section on the discussion of uncertainties does not comment at all on the clear possibility of confounding due to xylene exposures in the Finnish worker study. Also, there is no discussion of the possible magnitude or direction of any exposure misclassification bias in the Taskinen et al. (1999) study. If the Agency is going to use the Taskinen et al. (1999) study in their economic analysis, more attention to a description and discussion of the study's strengths and weaknesses is needed. 
EPA has clarified that the linear function is preferred.

EPA has clarified the text, and now only one figure is presented.

EPA has expanded the uncertainties discussion regarding the Taskinen et al. study to address these and other issues.
Rebecca T. Parkin, Ph.D., MPH
Exposure measurements were available only for the middle of the study period, but the authors were able to verify "most" women's self-reported exposure levels based on data from their workplaces.  The article does not state whether this verification was completed to the same extent across the entire study period.  This reviewer also wonders whether for some women (outside of the undefined "most") the authors assumed that self-reported HCHO exposure levels were accurate and did not change during the study period.  The Agency draft notes general exposure measurement concerns and agrees with Taskinen et al. regarding their modest response rate to the mailed questionnaire.  
 
Although Taskinen et al. note that reporting biases may be present in their study, they did not report any evaluation of their data to address that concern.  For example, the response rates for women with pregnancies in the 1985-90 vs. 1991-95 periods were quite different.  Although the authors note that "only a few women could not report the length of time to pregnancy," they do not indicate whether more women in the earlier vs. later period were non-reporters.  Also, there is no mention to what extent the authors believe the recall of the number of months-to-pregnancy was accurately recalled by either group of women.  Neither Taskinen et al. nor EPA adequately discuss whether self-reported time-to-pregnancy (or spontaneous abortion) data are reliable for use as an outcome measure.  If outcome misclassification is an issue as well as exposure misclassification, the odds ratios could be further compromised toward the null.  Discussion of the reliability of self-reported outcome data should be considered for the next draft.

The Agency's adjustment for non-occupational HCHO exposures, based on contemporaneous data, shifts the relationship to the right (from Figure 6 to Figure 7) but does not consider the variation in exposure levels found by Jurvelin et al.  The draft assumes that all of the women in the study had the same non-occupational HCHO exposures.  Considering the range, not just the mean, of Jurvelin et al.'s measurements would be more informative and would allow for the identification of upper and lower bounds on the concentration-response relationship.  

EPA has added some discussion about errors in outcome reporting.

For the purposes of this document, EPA was primarily concerned with "best estimates" for the exposure-response relationships
III.  SPECIFIC OBSERVATIONS ON THE DOCUMENT
                                     NAME
                                    COMMENT
RESPONSE
John R. Balmes, M.D. 
Page 10, 1[st] full paragraph; page 14, figure 4a legend; page 15, 2[nd] full paragraph.  The use of "inhalation" exposure in the context of eye irritation seems inappropriate.  I would eliminate the use of "inhalation" in all three sentences.

Page 16, paragraph. 2.2.1.  Asthma is defined by the Global Initiative for Asthma (GINA) as a disease characterized by inflammation of the airways, not lungs.  I would eliminate "and lungs" in the first sentence of this paragraph.  To avoid confusion, I would not use "sensitization" when discussing non-allergic, neurogenic mechanisms of irritant chemical-induced asthma in the third sentence.

Page 20, paragraph 2.3.1.  "Increased relative risk estimates (RRs) were in the range of 1.7 to more than 3.0." To avoid confusion, I would cite the specific papers that reported these increased relative risks.

Page 22, last sentence of text.  The text here refers to "estimated concentration-response functions" but does not explain why there is more than one CRF in Figure 6.  It is not until page 24 that one learns that "Regression equations for linear and exponential fits are also provided."  If the two lines in Figures 6 and 7 are for both types of fits then this should be clearly indicated.

Page 26, last full sentence.  The use of a contraction here ("didn't") is unprofessional.
EPA has eliminated the use of the word "inhalation" in the context of exposures resulting in eye irritation.

EPA has made these revisions to the first paragraph on asthma.

These studies are cited.

EPA has added a sentence identifying the use of both models before the figure appears.

EPA has changed "didn't" to "did not".
David Kriebel, Sc.D.
Page 20, section 2.3.1, 6[th] and 7[th] lines. The statement "Increased relative risk estimates (RRs) were in the range of 1.7 to more than 3.0" is not helpful  -  without explaining whose risk is being compared to whose, the absolute value of an RR is not useful. 

Section 2.0 Background on the Identification of Non-Cancer Health Effects, last sentence. It would be helpful to summarize at least briefly the logic behind focusing on these 3 endpoints. If I have understood the NAS comments correctly, that Committee also raised questions about these choices, and in particular on the decision not to use pulmonary function evidence. Given this concern from the NAS, I think a bit more explanation of the perceived inadequacies in the data for the other endpoints would strengthen this document. 
EPA has clarified this.

EPA has expanded its discussion of endpoint selection and specifically stated why pulmonary function data were not used.
Frederick J. Miller, Ph.D., Fellow ATS
None.
No response required.
Rebecca T. Parkin, Ph.D., MPH
Eye Irritation 

Page 10, last paragraph, line 4 and Figure 2, line 2.  The EPA draft states that these samples were taken from 30-60 minutes, but the authors only mention pumps running "for approximately one hour" (p. 1026).  Does EPA have information in addition to what is in the article or is the 30-minutes an error?  

Pages 11-12.  Figure 2 in the draft has a more detailed caption, but otherwise seems to be exactly the same as the one in the Hanrahan et al. paper (which is data for "burning eyes"); is it the same as in the paper?  If so, shouldn't it clearly indicate that it is "burning eye" data?  

Page 12.  Table 1 may need a clearer caption indicating whether the data shown are for "burning eyes" AND "eye irritation" or "eye irritation" alone.  Wherever combined data are used, EPA should clarify this usage and possibly create a new name for combined eye symptom data.   Further, the title of Table 1 would be more accurate if it included "...extracted and calculated from..."  

Asthma

Page 16, last paragraph, last 2 lines and top of page 1.  The descriptive language in the Agency draft about using the McGwin et al.'s I2 statistic would be stronger if made more specific; e.g., noting that McGwin et al. used a cut-point of <50% for choosing fixed- vs. random-effects data (page 314, top of middle column).  It appears that EPA agreed with this cut-point.  

Page 18, first complete paragraph, line 6.  The Agency states that the I2 statistic is 11.2 when the Rumchev et al. paper is excluded, but Table 2 in McGwin et al. shows 11.3.

Female Reproductive Toxicity

Page 22.  The title on Table 2 should state which "response" (TTP) is presented.

EPA has corrected this.

EPA has re-titled the figure to indicate that the data are for "burning eyes".

Table 1 presents data EPA extracted from Fig 2, which has been re-titled to indicate that the data are for "burning eyes".

EPA selected the random-effects model and has provided a rationale for this choice.

This has been corrected.

The response has been added to the title.

      VI.	PEER REVIEWER COMMENT TABLE ON THE BENEFITS ASSESSMENT APPROACH
                                       
                            I.  GENERAL IMPRESSIONS
                                     NAME
                                    COMMENT
                                   RESPONSE
Glenn C. Blomquist, Ph.D.
Overall, the draft Approach Document is well-written.  Refreshingly, Standard English language is used extensively and technical terms introduced when necessary.  Examples to explain terms such as odds ratios should make the document understandable to educated lay readers with varied backgrounds.  The key concentration-response functions are clearly presented in the form of equations and graphs or tables.  This draft is readable.  Information presented appears to be accurate and representative of studies that are the source of the information.  Brief descriptions of key studies are given in addition to the findings relevant to the topic of this draft Approach Document.  The extensive list of references allows the reader to learn more about the studies from which crucial estimates are taken.  Conclusions regarding concentration-response functions and valuation (monetization) as reflected in their use in the examples follow from the information and models presented in a logical and reasonable way.  My assessment of presentation applies to the entire document.  My assessment of accuracy and soundness applies mostly to Section 3 Benefits Assessment Approach because of my background in environmental and health economics.

No response required
A. Myrick Freeman III, Ph.D.
The general model for aggregating over time and across individuals that is outlined in Section 3.1 is correct.  For other "impressions," see my responses to specific charge questions below.
No response required
Shelby Gerking, Ph.D.
The report is, for the most part, complete and clearly written.  I had no problem following the narrative, however, an executive summary, a conclusion and a map of the climate zones would have been helpful.   

Also, in Section 3, there are at least seven issues that warrant additional thought.  First, the choice of the 3% discount rate, while not unreasonable, appears from out of nowhere.  Some attention needs to be given to this choice as well as to the assumption of exponential discounting.  Other types of discounting considered by behavioral economists may also be appropriate.   

Second, the contingent valuation estimates of WTP for eye irritation are rather dated -- those obtained by Tolley et al. are 25 years old.  EPA still uses these estimates, but there have been a number of advances over the years in the application of stated preference methods aimed at reducing hypothetical bias which causes stated preference estimates to be too high.  

Third, the Dickie et al. estimates in Table J-10 may not be directly comparable to those of Tolley et. al. and Loehman et. al. in that they are based on the averting behavior method (which looks at actual purchases of goods), rather than on contingent valuation.   In any case, the narrative might usefully reflect the fact that sound willingness to pay estimates are elusive and that different methods of estimating WTP often give (very) different results.  

Fourth, both asthma and eye irritation estimates rely on transferring adult WTP estimates to children.  This procedure, which may be the only available option, may well lead to substantial inaccuracies.  Parents, for example, may be WTP more to reduce health symptoms for their children than they are WTP to reduce those same symptoms for themselves.  In any case, the issue of WTP for adults vs. WTP for kids (with citations to recent literature) should be a discussion point in the report.  

Fifth, the WTP estimates presented implicitly assume that switching to different building materials, or treating wood products to cut down formaldehyde off-gassing will not occur for the 30 year horizon analyzed.  Is this assumption reasonable?  

In this same vein, could health effects from formaldehyde off-gassing be lessened by providing particularly residents of new homes with information that would lead them to install better ventilation systems?  If so, the marginal cost of better ventilation (if such a strategy is appropriate) might then form the basis of a simple WTP estimate along the lines of the headache example given on p. 31.  

Sixth, the population by housing type and climate zone apparently are assumed not to change over the next 30 years, even though there have been major changes in population by housing type and climate zone over the past 30 years.  This assumption seems hard to defend, although as noted on p. 42 it would be a difficult task to predict these movements.   

Seventh, it would be helpful to develop the main features of the cohort x housing type x climate zone model in introductory Section 3.1.  It would be helpful in this section to explain about the assumptions underlying this approach (some of these are identified above).  This reorganization will clarify the narrative at a number of points and avoid misunderstandings created when readers simply encounter model assumptions in the explanation of results.
A map of climate zones was added.

A footnote was added justifying the 3% exponential discount rate.

An explicit point about the age of the Tolley values and hypothetical bias in CV studies has been added.

EPA, but the Dickie et al. results in J-10 are not actually used.

Recognition that parents may be willing to pay more for children has been added.

Actually, benefits occur immediately. The 30 time horizon is only to capture the benefits of the rule into the future.

This is possible, but unnecessary given that we have stated preference WTP values.

While a static population and housing type is hard to defend, at this time EPA is not able to predict changes in demographics at the required level of detail to assume something different.

The document now includes this reorganization.
                       II.  RESPONSE TO CHARGE QUESTIONS
CHARGE QUESTION 1: The concentration-response function for the prevalence of eye irritation is based on Hanrahan et al. (1984). While Hanrahan does not identify the relevant time period for this relationship, Liu et al. (1991) produced qualitatively similar results for a two-week time period. We assumed that the concentration-response relationship for eye irritation is for a two-week period and multiplied the concentration-response function times 26 to obtain the number of cases of eye irritation experienced in one year. 

The concentration-response curve used is non-linear, which means that the annual approach may not produce an exact measure of the benefits, but it is believed that the bias is probably relatively small given the small change in exposure.

Please comment on whether the concentration-response function is used appropriately in the benefits assessment approach.
                                     NAME
                                    COMMENT
                                   RESPONSE
Glenn C. Blomquist, Ph.D.
The change in exposure expected from the policy appears to be small relative to typical exposure.  It follows that the linear approximation implied by multiplication by 26 to obtain annual changes in number of cases of eye irritation should produce only a small bias.  It seems as reasonable as other approaches.

No response required
A. Myrick Freeman III, Ph.D.
It was used appropriately.

No response required
Shelby Gerking, Ph.D.
The non-linear concentration response function is appropriately used in the benefits assessment approach.  However, the approach used here appears to take no account of other sources of formaldehyde exposure, such as workplace exposures.  In any case, the policy-related reductions in formaldehyde exposure should be treated as reductions in total exposure, not simply reductions in home exposure.  This refinement may alter the benefits calculation given the use of a non-linear concentration response function.
EPA does account for other sources of exposure. The text has been amended to reflect this.
CHARGE QUESTION 2: The concentration-response curve is for an acute effect occurring at a time less than the one-year time step of the exposure model. The willingness to pay to avoid cases of eye irritation is calculated for each year of analysis by multiplying the number of cases in a year by the marginal willingness to pay value to avoid one case. This may produce biased results, but the direction of that bias is unknown.

On one hand, some studies have suggested that the willingness to pay per symptom-day declines as the number of symptom-days avoided increases. In other words, the value to reduce two symptom-days of some effect is less than two times the value for one symptom-day. Therefore, this approach may overstate the total value. 

On the other hand, this analysis only applies values to one symptom, eye irritation, largely because this is the only symptom for which an effective concentration-response curve was derived. However, there is evidence that there are other forms of minor eye, nose, and throat irritation associated with formaldehyde exposure. Since eye irritation is the largest of the median values from the Tolley et al. (1986) study, the values used here likely represent a lower bound on the true effect of multiple symptoms. A reasonable upper bound of the total effect for one symptom-day would be sum of the willingness to pay for one symptom-day of each effect individually.  

Please comment on whether the annualized approach as opposed to the lifetime approach is appropriate in this context.
                                     NAME
                                    COMMENT
                                   RESPONSE
Glenn C. Blomquist, Ph.D.
I admit to being confused by the statement that eye irritation has the largest of the median values in the Tolley et al. (1986) study.  (For full disclosure, I am one of et al.)  Much of that study was published in Tolley, Kenkel, and Fabian Valuing Health for Policy (1994) particularly in Chapter 4 by Kenkel, Berger, and me.  In Table 4.3A on page 88, the median values for willingness to pay to avoid an additional symptom day are $11 for coughing, $12.50 for eye irritation, $13 for throat irritation, and $14 for sinus congestion.  All three are similar, but eye irritation is not the largest.  It will not make much difference, however, if either of the other two is used instead of $12.50 for eye irritation.

Comparing results reported in Table 4.3A and Table 4.3B suggests that willingness to pay per symptom-day declines as the number of symptom days avoided increases.  For example, the median value for avoiding 30 symptom-days of eye irritation is $100 which is less than 30 times $12.50 (or $375).  This suggests that multiplying the $12.50 times the number of days of eye irritation avoided will bias the annual estimate for avoiding eye irritation upwards if there are multiple days for individuals.  Declining marginal willingness to pay for avoided illnesses is also found in the recent study, Bosworth, Ryan, Trudy Ann Cameron, and J.R. DeShazo. "Demand for Environmental Policies to Improve Health: Evaluating Community-Level Policy Scenarios" Journal of Environmental Economics and Management 57 (2009): 293-308.

Table 4 also shows willingness to pay values for avoiding combinations of symptoms in a day.  The willingness to pay values for avoiding combinations of symptoms in a day are less than the sums of the willingness to pay values for avoiding the symptoms separately.  The declining marginal value of adding another light symptom suggest that a reasonable upper bound of the annual value of the total effect for one symptom-day would be the sum of the willingness to pay for one symptom-day of each effect individually.

On page 34, the paragraph that begins with Tolley et al. (1986) is mostly correct.  (I am a coauthor on that Tolley report and the Berger et al. (1987) article.)  It is correct, as stated, that the mean willingness to pay to relieve one symptom-day of a light symptom was $25 - $50.  It is mostly correct, as stated, that Berger et al. report higher willingness to pay values for these same symptoms.  The difference is due to different samples.  The Tolley et al. values are based on a sample of 176 respondents, some of whom had experienced the symptoms and some of whom had not.  The Berger et al. values are based on a subsample of 119 who actually had experienced a symptom.  The mean values for the subsample that had experienced the symptoms are greater than for the full sample for five of the seven light symptoms, nearly the same for one, and less for the remaining one.  The mean value for eye irritation was $48.48 for the 16 who reported eye irritation whereas the mean value was $27.73 for all 176 who responded.  The values reported are in 1984 dollars in both the Tolley et al. report and the Berger et al. article.  The median value for eye irritation of $12.50 that Weitzel (1990) found is also reported in Tolley, Kenkel, and Fabian Valuing Health for Policy (1994) in Table 4.3 on page 88.  It is correct that it too is in 1984 dollars. 

On page 36, if the BLS Inflation Calculator is used to inflate the median value of $12.50 for eye irritation from 1984 dollars to 1999 dollars, the value is $20.03 as shown in Table J-10.  If the same is done for 1984 to 2006, the value is $24.25, which rounds to $24, as reported below Table J-10.

Two recent studies find that different lifetime risk profiles are valued differently;  see Nielsen, Jytte Seested, Susan Chilton, Michael Jones-Lee, and Hugh Metcalf. "How Would You Like Your Gain in Life Expectancy to Be Provided? An Experimental Approach" Journal of Risk and Uncertainty 41 (December 2010): 195-218 and Cameron, T.A., J.R. DeShazo, and P. Stiffler. "Demand for Health Risk Reductions: A Cross-national Comparison between the U.S. and Canada" Journal of Risk and Uncertainty 41 (December 2010): 245-273.  Given the limited information on the symptoms of interest it is not clear how incorporate these finding into the Approach Document.
The statement that eye irritation is the largest median value is incorrect. EPA has corrected this in the text.

EPA has recognized in the uncertainties section and added the reference.

EPA has included this statement in the uncertainties section

Thank you for this clarification. EPA has revised the text accordingly and added the reference. Since the Tolley, Kenkel, and Fabian is the primary reference to the median values, the reference to Witzel has been removed.

No response required

These are interesting articles but EPA agrees that it is unclear how we would incorporate them.
A. Myrick Freeman III, Ph.D.
I don't understand the question.  What do you mean by the "lifetime approach"?  If you mean the results shown in Table 3 on p. 42, then either approach is appropriate.  They are just different ways of summarizing the data.
Reference to  the "lifetime approach" was designed to be contrasted with adding up benefit year-by-year, described as the "annual approach" in the text. However, EPA agrees with the reviewer's comment that they are just different ways of summarizing the data.
Shelby Gerking, Ph.D.
A search of the review document turned up no references to "lifetime approach", so the issue to be addressed here is not entirely clear.  

Nonetheless, it is likely that WTP per symptom day of eye irritation falls as the number of symptom days increase.  This outcome would be a general implication of utility maximization under a fixed budget.  As additional resources are spent to relieve eye irritation, the opportunity cost of foregone consumption will increase.  If eye irritation is coupled with other symptomatic discomforts, then we may have a different problem.  On the one hand, suppose that there exists a good that will reduce eye irritation together with all of the other symptoms.  Then, the marginal cost (inclusive of both time and money) of using the good to reduce these symptoms will be the WTP for all combined.  On the other hand, if more than one good needs to be purchased to reduce all of the symptoms, then the WTP would be the marginal cost of the combination of goods that will do the job.  In any case, it is problematic to simply add up CVM estimates of WTP for individual symptoms as this is likely to yield a total WTP value that really is upward biased.  Note that the CVM estimates themselves are probably upward biased.  
Reference to  the "lifetime approach" was designed to be contrasted with adding up benefit year-by-year, described as the "annual approach" in the text.

The text regarding diminishing marginal WTP and adding estimates has been revised in the uncertainties section.
CHARGE QUESTION 3: The concentration-response function for the prevalence of eye irritation is for a single two-week period.  The annualized approach used an adjusted concentration-response relationship that consisted in multiplying the concentration-response function obtained from Hanrahan et al. (1984) by 26 two-week periods.
   
Please comment on whether the adjustment of the concentration-response function is appropriate in the annualized approach.
                                     NAME
                                    COMMENT
                                   RESPONSE
Glenn C. Blomquist, Ph.D.
It seems as reasonable as other possible approaches.

No response required
A. Myrick Freeman III, Ph.D.
Yes, it is appropriate.

No response required

Shelby Gerking, Ph.D.
An issue here is that there appear to be different ways to interpret the Total WTP expression on p. 39.  Should we assume that the same people experience eye irritation repeatedly for each 26 two-week periods in the year?  If this (Groundhog Day) assumption is correct, then the WTP value applied may well be on the high side.  On the other hand, if we assume that a different set of people experience these symptoms in each of the two week periods, then the calculations presented may be more defensible.  
EPA has included this comment in the uncertainties section.
CHARGE QUESTION 4:  The concentration-response relationship for asthma incidence is given as an odds ratio for children exposed to formaldehyde. An odds ratio is a way of comparing the difference in the probability of an event, in this case asthma diagnosis, occurring in groups exposed at different levels. The odds ratio is used to determine the willingness to pay for any change in emissions exposure over a 16 year period. We assume that the probability of being diagnosed with asthma is uniformly distributed across these 16 years. 

The use of an odds ratio implies that the concentration-response relationship is non-linear. However, given that the change in exposure is relatively small, the results from using this implied non-linear function are anticipated to be similar to the results if we were to use a linear function.

Please comment on whether the concentration-response function is used appropriately in the benefits assessment approach.
                                     NAME
                                    COMMENT
                                   RESPONSE
Glenn C. Blomquist, Ph.D.
It seems as reasonable as other possible approaches.

No response required
A. Myrick Freeman III, Ph.D.
It was used appropriately.
No response required
Shelby Gerking, Ph.D.
I agree that the bias from using the implied non-linear function is likely to be small, but please see #1 in the eye irritation section for a possible qualification.
EPA assumes that the reviewer is referring to the concern about accounting for other sources of exposure. EPA does account for these sources. The text has been amended to reflect this.
CHARGE QUESTION 5:  The valuation of asthma effects from formaldehyde exposure is based on valuing the incidence of asthma rather than the more standard valuation based on the exacerbation of asthma symptoms. The reason for this is that a statistical relationship between formaldehyde exposure and asthma exacerbation has not been sufficiently well established, but there is a statistical relationship between formaldehyde exposure and asthma occurrence or incidence. However, the only time that EPA has valued asthma exacerbation is for the first prospective study of the benefits and costs of the Clean Air Act (EPA 1999). This is probably due to a lack of an appropriate concentration-response relationship. The EPA's Office of Air does include recommended values for the monetization of chronic asthma in its BenMAP documentation (EPA 2011b), which is based on an average of the results from Blumenschein and Johannesson (1998) and O'Conor and Blomquist (1997).

For this analysis, EPA treats prevalence as a measure of cumulative incidence by assuming that the disease duration is the rest of the child's life. However, the EPA (2000a) has previously assumed that a portion of asthmatic children will become asymptomatic as they move into adulthood.

Please comment on whether the annualized approach as opposed to the lifetime approach is appropriate in this context.

                                     NAME
                                    COMMENT
                                   RESPONSE
Glenn C. Blomquist, Ph.D.
The approach used seems reasonable except for ignoring that some of the asthmatic children are likely to become asymptomatic as adults.  If the incidence and prevalence data can support outgrowing asthma, then it should be incorporated in the estimates of valuing the incidence of asthma.  Otherwise, the estimates will be biased upward.

I agree with the choice of the best estimate from O'Conor and Blomquist (1997) for the implied annual value of asthma control (page 47).  It is $1,474 and is based on the risk-risk tradeoff and the assumed value of statistical life of roughly $6 million.  The $1,474 is close to the nonparametric estimates of $1,500 for the 5 unit change and $1,440 for the 10 unit change.  It is also close to the parametric estimates assuming a value of statistical life of $6 million of $1,468 for Model 3 and $1,504 for Model 4.  They are the more complete specifications of the drug choice logistic regression.  Since surveys were done in 1995, the values are in 1995 dollars.

The implied annual value of asthma control of $1,474 in 1995 dollars is also close to the best estimates from our more recent work; see Glenn C. Blomquist, Mark Dickie, and Richard M. O'Conor. "Willingness to Pay for Reducing Fatality Risks and Asthma Symptoms:  Values for Children and Adults of All Ages" Resource and Energy Economics 33 (May 2011): 410-425. In this recent work, we are able to estimate the willingness to pay without assuming a value of statistical life.  As Table 5 shows, for the ordered logistic regression for willingness to pay for the more effective drug we have a larger sample for the preferred specification (263 in 2011 > 75 in 1997) and the ratio of the coefficient for efficacy in controlling asthma to its standard error is much larger (3.14 in 2011 > 0.70 in 1997).  This facilitates estimation directly from the willingness to pay logit rather than indirectly from the risk-risk logit and an assumed value of statistical life.  We were also able to test for selection bias related to the choice of drug at the first stage of the hybrid contingent valuation.  (We found we could not reject the null of no correlation between errors and so based estimates of willingness to pay on the logit regression without selection.)  Lastly, we made estimates based on using only "definitely yes" as a "yes" instead of both "definitely yes" and "probably yes" as a "yes" as in O'Conor and Blomquist (1997).  In Table 6 we report values that turn out to be comparable to the best estimate from our earlier work.  For the average age adult (45 years) our estimate for the annual value of asthma control is $1,960 in 2007 dollars (or $1,441 in 1995 dollars).  

From Table 6 which reports annual values of asthma control by age we cautiously summarize saying that the pattern of results hints that values are higher for children and young adults.  For the average age child (11 years) our estimate for annual value of asthma control is $2,842 in 2007 dollars (or $2,089 in 1995 dollars.)  This pattern is relevant for estimating the asthma related benefits because the ages considered are 0  -  16 and point estimates for values for children are greater than the value for the average age adult.  The pattern suggests that estimates based on the average value for adults are probably underestimates, at least with respect to this factor.
The monetization section has been revised to include the children who become asymptomatic.

The values have been updated to 2010 dollars.

Reference to this work has been added.

The monetization section has been revised to more accurately reflect the higher value for children. 
A. Myrick Freeman III, Ph.D.
Again, I don't understand the question.  What do you mean by the "lifetime approach"?  The term is not used in the document.
No response required.
Shelby Gerking, Ph.D.
A search of the review document turned up no references to "lifetime approach" so the issue to be addressed here is not entirely clear.  

Nonetheless, the report makes clear that valuation of asthma effects is based on valuing the incidence of asthma, rather than symptom exacerbation.   This approach is crude for two reasons.  First, there is substantial heterogeneity in cases of asthma.  For some people, asthma is little more than an annoyance, while for others this illness is debilitating.  Willingness to pay to avoid asthma would be expected to vary according to how serious a case is contemplated.  

Second, willingness to pay to reduce additional cases of asthma will not include the willingness to pay to reduce exacerbated symptoms of those who already have asthma.   

Two other issues: (1) While estimates of increased incidence of asthma pertain to children (see p. 19), estimates of WTP to reduce asthma incidence are based on two studies of adults.  Parents may well be willing to pay more to reduce asthma incidence among their children than they are WTP to protect themselves from the same illness.  

(2) It might be useful to perform a sensitivity analysis on the estimates provided to determine how much difference it would make to assume that a percentage of childhood asthmatics become asymptomatic when they become adults, rather than assume that childhood asthmatics carry their illness forward to adulthood.  
Reference to the "lifetime approach" was designed to be contrasted with adding up benefit year-by-year, described as the "annual approach" in the text.

This is a reasonable concern but neither the concentration-response function nor the valuation distinguish the level of severity of asthma. Therefore, this adjustment cannot be made.

At present, a defensible concentration-response function cannot be derived for this endpoint, so it is not valued in this analysis.

The monetization section has been revised to more accurately reflect the higher value for children.

The monetization section has been revised to include the children who become asymptomatic.
CHARGE QUESTION 6: The concentration-response relationship is based on an odds ratio for a period of time longer than the one year. The exposure model produces results for one-year of exposure to formaldehyde for each age, housing type, and climate cohort. As a consequence, an adjustment to the simple model needed to be made to model the effect on individuals who are currently alive when the regulation takes effect.

As an upper bound estimate, we assume that the odds ratio can be applied to the one year reduction in the same fashion as it was applied for the 16 year time period. The problem with this approach is that it effectively treats the exposure as an acute effect. If the odds ratio indicates a particular percentage reduction in asthma cases from a reduction in formaldehyde exposure over 16 years, the upper bound approach would suggest the same percentage reduction in asthma case in one single year if we were to witness the same reduction in formaldehyde exposure in one year. The lower bound approach assumes that a particular exposure reduction for one year produces the same effect as if that exposure reduction were spread out over the entire 16-year time period. 

Please comment on the upper and lower bound methodology used.
                                     NAME
                                    COMMENT
                                   RESPONSE
Glenn C. Blomquist, Ph.D.
It seems as reasonable as other possible approaches.

No response required.
A. Myrick Freeman III, Ph.D.
The approach seems reasonable.  The bounds are relatively narrow, as shown in Table 7.  How will the results be presented in the final report, as upper and lower bounds or averaged to give a "best" estimate?
Reference to the "lifetime approach" was designed to be contrasted with adding up benefit year-by-year, described as the "annual approach" in the text.
Shelby Gerking, Ph.D.
The upper bound estimates are obtained by assuming that asthma onset is an acute effect of formaldehyde exposure particularly among older teenagers.  I am uncertain as to whether this assumption is at variance with scientific information regarding the development of this disease and would defer to another panel member with greater expertise on this point.  If asthma onset from formaldehyde exposure cannot be considered an acute effect, then the upper bound estimates would be less credible.  Nonetheless, the upper bound estimates and the lower bound estimates do not differ greatly.  Table 7 reports that for the three housing profiles total discounted upper bound WTP is $4,939,166 and the corresponding lower bound figure is $4,340,740.  So, the upper bound estimate is about 14% larger than the lower bound estimate.  

An alternative to the lower bound estimate might be to assume that currently living children are unaffected by reduced formaldehyde exposure.  Instead, we might assume that the reduced exposure applies only as "new" children as they enter the model.  These "new" children are then assigned cases of asthma with the incidence rates described on p. 48 of the review document.  
EPA does not have a definitive model of the development of asthma, so this upper bound is, at minimum, possible.

This would, indeed, produce an even lower bound, but it would require assuming that there are no benefits to formaldehyde reduction unless one experiences 12 full years of that reduction. Given that this would be a very extreme assumption, this new lower bound has not been estimated.

CHARGE QUESTION 7: The prevalence data suggest that 7.2% of children age 0-4 have been told that they have asthma. 16.4% of children aged 5-14 have been told that they have asthma. We assume that the probability of being diagnosed is uniformly distributed across the 0 to 16 age bracket, so that the incidence rate would be 1.44% for the first five years and 1.49% for the next eleven years. Allocating cases uniformly across the age brackets provides us with a way to calculate the annual benefits of any exposure reduction that occurs for the entire time period, but may not be appropriate if the diagnosis of asthma for very young children (e.g., age 0-2) differs from older children.

Is the assumption about applying the concentration-response function to children aged 0 to 16 appropriate, given the asthma onset studies' focus on school-aged children and adolescents, and given the potential uncertainty of the Rumchev study involving younger children?
                                     NAME
                                    COMMENT
                                   RESPONSE
Glenn C. Blomquist, Ph.D.
It seems as reasonable as other possible approaches.  

A question about this and the other concentration-response functions and exposure is whether or not they take into account averting behavior.  Smell leads to open windows and more time outside of house and less exposure.
No response required.

The concentration response functions were developed using in-home samples which, implicitly, included the averting behavior of the home participants. However, averting behavior changes (e.g., reduced smells leading to fewer open windows) were not included in the economic analysis.
A. Myrick Freeman III, Ph.D.
I can't answer this.  It lies outside my area of expertise.

No response required.
Shelby Gerking, Ph.D.
I defer to another panel member here as I have no expertise in this area.  
No response required.
CHARGE QUESTION 8: The linear concentration-response function accounting for background exposures based on Taskinen et al. (1999) is used for the annual approach.

Please comment on whether the concentration-response function is used appropriately in the benefits assessment approach.
                                     NAME
                                    COMMENT
                                   RESPONSE
Glenn C. Blomquist, Ph.D.
It seems as reasonable as other possible approaches.

No response required.
A. Myrick Freeman III, Ph.D.
It was used appropriately.

No response required.
Shelby Gerking, Ph.D.
The concentration-response function appears to have been applied correctly in the benefits assessment approach.  

Note that the concentration-response function is linear, so accounting for other sources of formaldehyde exposures would be less important.  However, two other issues might be addressed.  First, equations (18) and (19) in the text may require some clarification.  My question relates to the term .  Does a = ?  Does b = ?  If so, the notation should be changed.  If not, the equation needs additional explanation.  

Second, in these equations, population refers to women who have difficulty conceiving.  The population of women who are actively attempting to become pregnant would instead be more appropriate.  Page 59 indicates that for the proposed rule this latter definition would be incorporated.  I agree that this change would be appropriate.  
No response required.

EPA does account for other sources of exposure.

You are correct that a = and b = . The notation has been changed.

The model has been revised to use  women who are seeking pregnancy as the appropriate population.
CHARGE QUESTION 9: Monetization of delayed fertility has been discussed in the literature but has never been included in primary analyses of EPA rules because it was believed that the scientific knowledge on reproductive and developmental health effects was not strong enough to quantify risk in the primary benefits analysis.

While there appears to be good data on the cost of treatment, there are few studies on the willingness to pay to reduce delayed conception. Most economic valuation studies regarding fertility focus on an individual's or a couple's willingness to pay for infertility treatment, particularly in-vitro fertilization (IVF).  Conceptually, the willingness to pay approach is preferable and could be deduced from the valuation studies. However, given that there has been less research on these willingness to pay values than other values and the fact that the values have not been used in previous economic analyses, we used the more straight-forward cost of illness approach for this analysis.

As an upper bound, we assume that any woman who has difficulty conceiving (i.e., time to pregnancy exceeds 12 months) will obtain some type of fertility service. This may be a reasonable upper bound, but there are certainly women who have trouble becoming pregnant and do not seek fertility treatment. 

The willingness to pay for fertility treatment is treated as an expected value. The average cost of various cycle-based fertility treatments is multiplied times the probability of obtaining that treatment at various ages. There is probably a small opposite effect associated with an increase in pregnancy from reduced formaldehyde exposure by women who do not want to become pregnant, but we do not consider this effect

Please comment on whether the annualized approach as opposed to the lifetime approach is appropriate in this context.
                                     NAME
                                    COMMENT
                                   RESPONSE
Glenn C. Blomquist, Ph.D.
It seems as reasonable as other possible approaches.

On page 58, the choice is made to use the cost-of-illness estimates from Katz et al. (2011) for valuing difficulty in conceiving due to formaldehyde exposure.  A strength of these estimates is that apparently most fertility treatment costs are paid for out-of-pocket by consumer/patients rather than by third parties through private or public insurance.  As such, consumers reveal that the treatments are worth at least as much as they paid.  Their maximum willingness to pay would be expected to be greater than these costs because of consumer surplus.  (This does not take into account any utility or disutility of treatments.)  If data were available and demand for fertility treatment could be estimated, then a better estimate of maximum willingness to pay could be made.  This suggests using cost-of-illness will produce an underestimate.  However, if the values are applied to all women who are exposed to formaldehyde, benefits will tend to be overestimated.  The reason is that not all the women whose fertility is affected will pay the market prices for the treatments.  In other words, the price is known for the various packages of treatments, but the number of women who are willing to pay the price is not.  The maximum willingness to pay for treatment for the women whose fertility is affected but choose to forgo treatment and the number of them are unknowns.  Their values are likely to be positive, but they are less than the costs.  Katz et al. report treatment costs per successful outcome of more than $70,000.  They also report that 72% of the women had college education.  A hunch is that those women have above average household incomes and spend most of their time in single family detached homes where exposure reduction is smallest.  Less educated women with lower household incomes are probably less likely to pay for treatments at the going prices.  Assuming that women who have below average incomes and live in mobile homes will pay the market prices for the same distribution of fertility treatments is likely to bias the estimate of benefits of reducing exposure to formaldehyde upward.
No response required.

An explicit discussion of this point has been added to the uncertainty section.
A. Myrick Freeman III, Ph.D.
Again, I don't understand the question.  What do you mean by the "lifetime approach"?  The term is not used in the document. 

Perhaps the charge question should be "Please comment on the annual approach to calculating a total WTP per year as described in Section 3.4.2."  My answer to that question is that if a valid individual WTP per year can be obtained, equation (18) is the appropriate way to calculate aggregate WTP per year.  But for reasons I point out in the Specific Observations section below (see my comments to question #3), I have serious doubts about the ability to obtain a valid individual WTP per year.
Reference to the "lifetime approach" was designed to be contrasted with adding up benefit year-by-year, described as the "annual approach" in the text.

EPA believes that there is sufficient data to monetize this endpoint, so we have included this estimate. However, the concerns that the reviewer raises are very important. The uncertainty section for this endpoint has been expanded and these point have been explicitly included in the text.
Shelby Gerking, Ph.D.
Cost-of-illness estimates are conceptually inappropriate in this context for two reasons.  First, cost-of-illness is not a conceptually sound approach for estimating willingness to pay.  This point is noted in the document on p. 58.  In consequence, I would suggest that cost-of-illness estimates might be used only as a last resort.  The WTP estimates obtained by Smith and van Houtven may well be a more defensible choice.  Careful thought should be given to whether this alteration would be an improvement.  Second, the COI estimates utilized (see equation (20) and Table 10) do not really pertain to the delay in conception addressed in the Taskinen study.   Women (or couples) may be willing to pay to reduced time to conceive, but may at the same time be reluctant to seek fertility treatment.  At a minimum, this potential misalignment should be addressed.  
This point was explicitly recognized in the uncertainties section.
CHARGE QUESTION 10: The time period associated with the exposure-response function is longer than the time step of the exposure model. The Taskinen (1999) study examined the fecundity of women age 20-40. This causes a problem if we have an individual who does not experience the exposure reduction for the full time period. We can form an upper and lower bound of this willingness to pay as we did for asthma prevalence. The upper bound is based on the assumption that the linear concentration-response function holds for an acute exposure of one year. The lower bound assumes that an exposure reduction for one year represents 1/20[th] of an exposure reduction for the entire 20-year time period. 

Please comment on the upper and lower bound methodology used.
                                     NAME
                                    COMMENT
                                   RESPONSE
Glenn C. Blomquist, Ph.D.
It seems as reasonable as other possible approaches.

No response required.
A. Myrick Freeman III, Ph.D.
The approach seems reasonable.  How will the results be presented in the final report, as upper and lower bounds or averaged to give a "best" estimate?
No response required.
Shelby Gerking, Ph.D.
The Taskinen study appears to treat formaldehyde exposure as a long term exposure.  In consequence, I am uncertain that the upper bound estimates are defensible (see the related point #6 in asthma above).  Nonetheless, the upper and lower bound WTP estimates differ only by about $57,000 (see Table 12).  This outcome could change of course if the analysis is redone along lines suggested above.  

Also, as with asthma, I would suggest the possibility to treat "new" women entering the model as those affected by the contemplated reduction in formaldehyde exposure.
EPA does not have a definitive model of the development of asthma, so this upper bound is, at minimum, possible.

This would, indeed, produce an even lower bound, but it would require assuming that there are no fertility benefits from formaldehyde reduction unless a woman experiences 20 full years of that reduction. Given that this would be a very extreme assumption, this new lower bound has not been estimated.
CHARGE QUESTION 11: The ages used in this analysis reflect the ages reported in the Taskinen (1999) study, ages 20-40. However, women older than age 40 obtain fertility treatment. The value of reduced infertility effects from reduced formaldehyde exposure is not reflected in this analysis in order to remain consistent with Taskinen (1999).

Please comment on whether the concentration-response function was applied to appropriate age groups given the age groups in the studies. 
                                     NAME
                                    COMMENT
                                   RESPONSE
Glenn C. Blomquist, Ph.D.
It seems as reasonable as other possible approaches.

No response required.
A. Myrick Freeman III, Ph.D.
Given my reservations about using the cost-of-fertility treatment to monetize this effect (see  my comments to question #3 in the Specific Observations section below), I have no problem in limiting the quantification of this effect to the age group covered in the Taskinen study.
No response required.
Shelby Gerking, Ph.D.
The Taskinen study does not appear to provide a direct basis for adding women aged 40 and older to the analysis.  However, relatively few of these women may seek to become pregnant in a given year.  If the analysis focused on women who seek to become pregnant, exclusion of women over 40 years of age may not be a grave oversight.  I would defer to a panel member more knowledgeable about fertility issues to make a judgment on this issue.
Reference to the "lifetime approach" was designed to be contrasted with adding up benefit year-by-year, described as the "annual approach" in the text.
                  III.  SPECIFIC OBSERVATIONS ON THE DOCUMENT
                                     NAME
                                    COMMENT
                                   RESPONSE
Glenn C. Blomquist, Ph.D.
Page 53, bottom.  $4.9 instead of $4,9.

Page 56, 3[rd] paragraph.  Monetization is misspelled.

Page 58.  Van Houtven and Smith (1999) instead of 1997 and $12,500 instead of $12,50.

Page 59.  Is the probability of obtaining cycle-based fertility treatment shown in Table 8, the best projection for future treatment?  The utilization percentages given on page 916 in Katz et al. seem different.

Page 68.  O'Conor instead of O'Connor.

These edits have been included.

A more accurate method for estimating the probability of obtaining cycle-based fertility treatment has been added.

This edit has been included.
A. Myrick Freeman III, Ph.D.
There are a number of typographical and editorial errors.  This is not a complete list:

Table of Contents.  Page numbers are wrong.

Page 17.  Figure 2 should be labeled figure 5.

	Section 3.  Why do the table and figure numbers start over instead of continuing throughout the report?  And some of the table numbers seem to be wrong (e.g., J-10 on page 36).

Page 6.  The report gives the aim of developing concentration-response relationships as being " ... to inform the economic benefits assessment of potential cost savings ..."  This is not about "cost savings;" it is about welfare gains.

	In some places, coefficients in the concentration-response relationships are Greek letters.  In other places they are not.

Section 2.1.1, 3[rd] sentence in the first paragraph.  Needs editing.

Page 53.  Where it says "($93,095 + $58,662 + $90,852= $242,602)," it should be = $242,609.

Page 58.  It says "willingness to pay of between $3,750 and $12,50 for fertility treatment."

Page 59.  The probability of using IVF should be 2.5%, not .25%.

Page 61, last paragraph.  There are two references to Table 10, which should be Table 12.

Page 63.  The sentence, "This is probably the largest category of value associated fertility issue from a reduction in formaldehyde exposure," needs editing.
I have added the following three charge questions based on my expertise in non-market valuation:

(1) Please comment on the validity of the monetization of sensory irritation. The approach to the monetization of this effect is the same as that used in the First Prospective Section 812 Report.  In my judgement, this is a valid approach and makes the best use of the available empirical evidence.  

However, it should be noted that the effect actually valued in the  First Prospective Section 812 Report as "Upper Respiratory Symptoms" defined as "two or more of the following symptoms: runny or stuffy nose; coughing; and eye irritation."  Since this document states that formaldehyde can cause a variety of types of sensory irritation in the upper respiratory system (p. 7), this is appropriate.  But it should be made clear that more than simply eye irritation is involved.

(2) Please comment on the validity of the monetization of chronic asthma.  The approach to the monetization of this effect is the same as that used in the First Prospective Section 812 Report.  In my judgement, this is a valid approach and makes the best use of the available empirical evidence. 

(3) Please comment on the validity of the monetization of reduced fertility. I have serious reservations about the approach taken here to monetize this effect.  First, "reduced fertility" is not a well-defined effect.  There is ambiguity as to both the degree of reduction and its duration.  This makes determining the proper valuation difficult.  

I agree that conceptually, the willingness to pay (WTP) approach is preferable to a cost-of-illness or cost-of-treatment approach.  However, as I read the available WTP studies, they apply to the more serious infertility rather than to the "subfertility" (p. 21) associated with exposure to formaldehyde.  Thus, the available WTP studies are not suitable for benefits transfer.

The report takes a cost of treatment approach to valuation.  But it is not at all clear to me that the "cycle-based treatments" described here are either appropriate treatments or likely to be effective in the face of continued formaldehyde exposures.

For these reasons, I recommend that this effect be described and quantified to the extent that evidence supports quantification, but that it be acknowledged that there is not an adequate basis for monetization of this effect.

These edits have been included.

No response required.

Appendix H (pg. H-24) defines it as "one or more of the following: runny or stuffy nose, wet cough, burning, aching, or red eyes." This means that it is the same value used in the retrospective study. Nevertheless, EPA understands the reviewer's concern and has included the definition in the discussion of the retrospective study.

No response required.

These are important considerations and they have been explicitly included in the text. 

It is EPA's position, however, that there is sufficient data to monetize this endpoint.
Shelby Gerking, Ph.D.
The document appears to have been put together hastily as there are numerous typos and other glitches.  Below is a list of typos that I flagged -- I am certain there are more.

Page 31, first line below equation (1).   ...risk reduction at age a.

Page 35, next to last line of third full paragraph.  Data should be days

Page 36.  Not sure why the Table is called "Table J-10".  Other tables are not numbered this way.  Also, in this table Dickie et al. needs a date

Page 44, first line under monetization.  Analysis should be analyses.

Page 45, Table IV.  2-17 not numbered consistently with other tables, also in two places decimal points are mistakenly used for commas

Page 53, last full line.  Should be $4.9 million

Page 56, eighth line up from bottom.  Undergoes should be undergo

Page 57, fourth full paragraph, first line.  Ryan (1996) conducted a contingent ...

Page 58, first full paragraph, line 4.  Respondents were asked to consider taking...

Page 59, line 8 under equation (19) (and elsewhere).  The word data is plural, not singular

Page 59, line 12 under equation (19).  Difficulty is misspelled

Page 59, second line up from bottom.  Reduction is misspelled

Page 60, part of Table 9 appears to be missing.  Also, the heading is missing a number for ppb.

Page 60, Table 10.  The probability values are missing

These edits have been included.