Regulatory Toxicology and Pharmacology 58 (2010) 161–166

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Commentary

Formaldehyde and lymphohematopoietic cancers: A review of two recent studies

Philip Cole a, Hans-Olov Adami b, Dimitrios Trichopoulos b, Jack Mandel c,⇑a Department of Epidemiology, School of Public Health, University of Alabama at Birmingham, Birmingham, AL, United Statesb Department of Epidemiology, Harvard School of Public Health, Boston, MA, United Statesc Dalla Lana School of Public Health, University of Toronto, Toronto, Ontario, Canada

a r t i c l e i n f o a b s t r a c t

Article history:Received 16 April 2010Available online 22 August 2010

Keywords:FormaldehydeCancerEpidemiology

0273-2300/$ - see front matter � 2010 Elsevier Inc. Adoi:10.1016/j.yrtph.2010.08.013

⇑ Corresponding author.E-mail address: jack.mandel@utoronto.ca (J. Mand

Objective: : This paper reviews and evaluates two recent epidemiologic studies of formaldehyde exposureand lymphohematopoietic cancers. One is an update of mortality in a retrospective cohort study of indus-trial workers and the other is a proportional mortality and case-control study among embalmers. Bothstudies included subjects with considerable exposure to formaldehyde and both are focused on the mye-loid leukemias.Methods: The principal epidemiologic methods and analyses used in the studies are described and eval-uated. Additional measures of risk are presented.Results: Neither study reports a significant excess of mortality from any form of lymphohematopoieticcancer. However, both studies are interpreted by their authors as positive for an association betweenformaldehyde and the myeloid leukemias. This is based on weak and transitory associations seen in expo-sure–response analyses of relative risks. Issues are raised relating to the interpretation of these findings.Conclusion: There is no statistically significant absolute excess mortality from any lymphohematopoieticcancer in either study. The study of industrial workers showed only a weak and transitory relationshipbetween peak exposure to formaldehyde and the myeloid leukemias. Limited exposure–response rela-tionships for the myeloid leukemias in the case-control study of embalmers apparently have not beenanalyzed for statistical significance. These limited exposure–response relationships do not provide clearevidence of a causal relationship between formaldehyde and the myeloid leukemias.

� 2010 Elsevier Inc. All rights reserved.

1. Introduction

The carcinogenicity of formaldehyde for human beings has beenunder evaluation since the 1970’s. In 2006 the International Agencyfor Research on Cancer (IARC) categorized formaldehyde as a knownhuman carcinogen because of its perceived ability to cause cancer ofthe nasopharynx. In 2009 IARC also judged the evidence that formal-dehyde causes leukemia in human beings to be sufficient. IARC’srecent view relies on epidemiologic reports recently published byresearchers at the National Cancer Institute (NCI). This review de-scribes and evaluates these reports, one of industrial workers andthe other of embalmers. Emphasis is on the lymphohematopoieticcancers (LHCs), particularly the myeloid leukemias.

2. The industrial workers study

2.1. Overview

The findings of the largest and longest-running retrospectivecohort study of industrial workers exposed to formaldehyde have

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been published in three reports (Beane Freeman et al., 2009; Blairet al., 1986; Hauptmann et al., 2003). This study included 25,619workers at 10 plants that produced or used formaldehyde. About83% of these subjects were exposed to formaldehyde. Follow-upextends from as early as 1934–2004 and the median follow-up per-iod is 42 years in the latest report. 13,957 (54%) of the subjectshave died.

The first report by Blair et al. (1986) followed subjects through1979 and included 61 formaldehyde-exposed LHC decedents. Datafor all forms of leukemia were combined and the non-Hodgkinlymphomas were included in other categories of the LHCs. Thesegroupings make Blair’s results difficult to compare with those ofthe two later reports.

The second report by Hauptmann et al. (2003), extended follow-up through 1994 and included a total of 161 formaldehyde-ex-posed LHC decedents. This report states that, ‘‘No measurementsof peak exposure were available. . .peak exposures were thereforeestimated. . .from knowledge of the job tasks and a comparisonwith the 8-h time-weighted average”. The absence of data on peakexposure is crucial because this exposure index is the basis of thepositive interpretations of findings in both the second and the thirdreports of this study. Also, there are no data on any measure offormaldehyde exposure after 1980 in any of the publications.

Table 1SMRs for formaldehyde–LHC associations from three reports of the NCI industrialcohort study. Last year of follow-up.

Disease group 1979 1994 2004

All LHCs 86 93 94Non-hodgkin

lymphomas– 73* 85

Hodgkinlymphomas

142 132 142

Multiple myeloma – 111 94Leukemias 74 98 102Lymphoid – – 115Myeloid 84** 95** 90Reference Blair et al.,

1986Hauptmannet al., 2003

Beane Freemanet al., 2009

* The only statistically significant value; 95% confidence interval: 56–96.** Our estimate.

162 P. Cole et al. / Regulatory Toxicology and Pharmacology 58 (2010) 161–166

Subsequent to its publication, it was recognized that the sec-ond report was incomplete. It had failed to identify 1006 deaths,about 11% of the correct total. Corrected versions of the majortables in the second report are included in a supplement to thethird report (Beane Freeman et al., 2009). The corrected SMRsare about 15% higher than those originally reported but expo-sure–response relationships are reduced. Unless stated otherwise,reference to results of the second report refer to the correcteddata.

Our focus is on the current or third report of the industrialworkers study published by Beane Freeman et al. (2009). This re-port extended follow-up through 2004 and included a total of998,000 person-years of observation. LHCs caused 319 deathsincluding 286 among formaldehyde-exposed subjects. This reportincludes seven tables published online at the website of the Jour-nal of the National Cancer Institute. Three of these tables supple-ment the findings of the third report while the four othersprovide corrections of findings of the second report (Hauptmannet al., 2003).

The third report states that there is, ‘‘. . .a possible link betweenformaldehyde exposure and. . .particularly myeloid leukemia butalso perhaps Hodgkin lymphoma and multiple myeloma”. It alsostates that there was a transient excess of myeloid leukemia that,‘‘. . .could reflect a relatively short induction-incubation time. . .”for this disease.

2.2. Exposure and diseases

Several publications (Blair et al., 1986; Blair and Stewart, 1990;Stewart et al., 1986) describe formaldehyde exposure assessmentsof the NCI cohort. However, the current report (Beane Freemanet al., 2009) indicates that validation of exposure assessmentswas, ‘‘not possible”. In addition, the correlation coefficient betweenthe full-shift exposure estimates of formaldehyde levels and mon-itoring data for a sample of 21 jobs was only 0.5. The square of thecorrelation coefficient is 0.25 indicating that the exposure esti-mates used in the study describe only about 25% of the variationin the monitoring data.

The current report states that exposure misclassificationprobably was non-differential with respect to the occurrenceand causes of death and so the study’s findings would bebiased towards the null. This is correct for real associations.But, in a study of many possible relationships, non-differentialmisclassification may produce false-positive findings (Rothmanand Greenland, 1998). Indeed, the corrected data for the sec-ond report show that originally it had missed 17.5% of deathsamong non-exposed subjects but only 9.7% of deaths amongthe exposed.

Despite extremely limited exposure information, five indices offormaldehyde exposure were developed for each subject: (1) Esti-mated maximum peak exposure. (2) Average level. (3) Cumula-tive amount. (4) Cumulative number of peak exposures at orabove 4 parts-per-million. (5) Duration of employment in exposedjobs. Subjects were divided first into the non-exposed and the ex-posed. Exposed subjects were divided into groups with ‘‘low”,‘‘medium” or ‘‘high” exposure with respect to each index. No re-sults are given for indices 4 and 5. However, it is stated that nei-ther of these was related to risk of any form of LHC. The secondreport did not evaluate data for index 4 and presented null datafor index 5.

Data were evaluated for all the LHCs collectively (ICDs 200–209) and for various disease subgroups. This review is focused onfive reasonably specific disease groups: (1) The non-Hodgkin lym-phomas (NHLs). (2) The Hodgkin lymphomas (HLs). (3) Multiplemyeloma (MM). (4) The lymphatic leukemias (LLs). (5) The mye-loid leukemias (MLs).

2.3. Results

Seven standardized mortality ratios (SMRs) compared the ex-posed subjects’ LHC mortality rates with those of the general pop-ulation of the United States. These are shown in our Table 1 as areSMRs from both of the earlier reports (Blair et al., 1986; Haupt-mann et al., 2003). For all LHCs combined, the SMR was 94 witha 95% confidence interval (CI) of 84–106, hereafter shown as94(84–106). The other SMRs range from 85(70–105) for the NHLsto 142(96–210) for the HLs. These SMRs show that a large, maturecohort of subjects with moderate to high formaldehyde exposuresexperienced unremarkable mortality from LHCs.

Twenty-five disease-specific exposure–response analyses weredone: (five indices of exposure for each of the five specific diseasegroups). Two p-values for trend were estimated for each of the 25analyses; one included only exposed subjects while the other alsoincluded the non-exposed. All trend tests used the low exposuregroup as the referent.

The remainder of this discussion addresses three diseases thatthe current report represents are, or may be, associated with form-aldehyde. First, for MM, the SMR among exposed subjects was94(71–125) based on 48 decedents. Of the five exposure–responseanalyses conducted, only that for estimated peak exposure ap-proached statistical significance (p = 0.08). In view of these essen-tially null findings, it is not clear why it is suggested that there is anassociation between formaldehyde and MM. Nonetheless, there areinteresting and unexplained aspects of the findings for MM. First,the SMR of 178(99–322) among non-exposed subjects was higherthan that among the exposed (SMR = 94). Similarly, in all three ofthe exposure–response analyses presented, the relative risk (RR)for non-exposed workers was higher than that for any exposedgroup.

Other recent studies of formaldehyde exposure do not supportan association with MM. The United Kingdom cohort study (Cog-gon et al., 2003) of industrial workers with moderate to heavyexposures to formaldehyde was nearly null for MM with an SMRof 118(48–244). We find no data for MM in the American cohortstudy of formaldehyde-exposed garment workers (Pinkertonet al., 2004) but Beane Freeman et al. (2009) state that there wasno excess of MM in that study. The study of embalmers (Haupt-mann et al., 2009), reviewed below, presents one analysis relatingto MM, that for ever vs. never embalming. The result was an oddsratio (OR) of 1.4(0.5–5.6). There is no known chemical cause of MM(De Roos et al., 2006; Alexander et al., 2007).

With respect to the HLs, exposed subjects had an SMR of142(96–210) with 25 deaths observed, an excess of about sevendeaths. Both the first (Blair et al., 1986) and the second report(Hauptmann et al., 2003) from this study showed a similar excessof five or six HL deaths. If the HLs and the NHLs (with an SMR of 85)

P. Cole et al. / Regulatory Toxicology and Pharmacology 58 (2010) 161–166 163

are combined, thereby accommodating possible errors of mis-classification between them, the resulting SMR is 93(77–112).Turning to exposure–response findings for the HLs, a statisticallysignificant (p = 0.01) relationship was seen with peak exposure toformaldehyde and a marginally significant (p = 0.05) relationshipwith the average level of exposure. The other three indices of expo-sure were unrelated to the HLs.

Both the UK and the American study of formaldehyde-exposedworkers were negative for the HLs but together included only threedeaths observed and 6.4 expected. The study of embalmers (Hau-ptmann et al., 2009) included only eight HL decedents and theone analysis reported, for ever vs. never embalming, was null withan OR of 0.5(0.1–2.6). There is no recognized chemical cause of theHLs (Mueller and Grufferman, 2006).

The current report, just as the second report, gives most atten-tion to the MLs. The SMR for the MLs among exposed subjects,based on 44 decedents, is 90(67–121). Of five exposure–responserelationships evaluated, only the one for estimated peak exposureapproached significance (p = 0.07, when non-exposed subjectswere included). It bears emphasis that the SMR and the expo-sure–response relationships in the current, or third, report fromthe NCI study provide no statistically significant positive associa-tion of formaldehyde with the MLs.

It is not clear why the one marginal relationship of the MLs withpeak exposure is considered noteworthy when the MLs are unre-lated to the four other exposure indices. An explanation may liein a paper by Blair and Stewart (1990) describing the limited cor-relation among results for several measures of formaldehyde expo-sure in the first report by Blair et al. (1986). They suggested,‘‘. . .that selection of an inappropriate measure could mute expo-sure–response gradients”. They advised investigators to use severalexposure measures, ‘‘. . .in order to avoid false-negative findings”.This perhaps was justified by the thought that the most positive in-dex is the one that best overcame any null bias from exposuremisclassification.

The current report’s suggestion that formaldehyde is linked tothe MLs rests on the view that these diseases were associated withpeak exposure to formaldehyde in the early years of follow-up butthat this subsequently dissipated. (This is shown in supplementaryTable S5, not reproduced here.) That table shows that RRs for theMLs (for subjects with mid-level and high exposure to formalde-hyde) declined from about 3.8 to 2.5 to 0.7 over the three succes-sive follow-up intervals. It suggests that this decline may reflect,‘‘. . .a relatively short induction-incubation time for myeloid leuke-mia. . .”. This interpretation is based on supplementary Table S6(excerpted in our Table 2) showing RRs in relation to time sincefirst exposure (TSFE) to formaldehyde. The only elevated RR is2.4 (0.5–13.3) for the TSFE group 16–25 years. However, the refer-ent group includes only 3 decedents and has an unknown SMR.

Neither the first nor the second report from the NCI study sup-ported a causal relationship between formaldehyde and the MLs.The first report presented an SMR for all leukemia of 74(45–114).It did not present an SMR specifically for the MLs but, using datain the online supplement to the third report (Beane Freemanet al., 2009), we estimated that SMR to be 84 (45–144). The secondreport did not provide an SMR for the MLs but others (Cole and Ax-ten, 2004) estimated it to be about 85 (uncorrected data) and we

Table 2Relative risks and numbers of deaths for the myeloid leukemias according to timesince first exposure to formaldehyde. From the supplement to Beane Freeman et al.,2009. Time since first exposure (years).

0 >0–15 16–25 26–35 36+

Relative risk 0.3 1.0 2.4 0.8 0.7Deaths 2 3 11 8 24

estimate it to be about 95 in the corrected data. There was one sta-tistically significant (p = 0.02) exposure–response analysis for theMLs in the second report, that with peak exposure.

No data for the MLs were provided in the UK study (Coggonet al., 2003). The study of American garment workers (Pinkertonet al., 2004) reported an SMR of 144(80–273) for the MLs. Thisstudy suggested an association between formaldehyde and theMLs among long-term workers. However, this finding was basedon an unconventional analysis using multiple causes of death foreach subject.

2.4. Interpretation

Among all three reports from the NCI cohort study of indus-trial workers, including the corrected and supplementary data,there are only two statistically significant findings for the MLs.One relates to peak exposure in the second report and one toTSFE in the third. The total number of significance tests (includ-ing confidence intervals) relating to the MLs that were done inthe two reports was at least 40. None of the SMRs was greaterthan 95 and only one of the exposure stratum-specific RRs wasstatistically significant. Nevertheless, Beane Freeman et al. statethat their null results for the MLs in the third report support acause-effect relationship between formaldehyde and the MLs.They suggest that this is because their null findings, ‘‘. . .couldreflect the increased precision of the relative risk estimates. . .(asmore data accumulated) or. . .a relatively short induction–incu-bation time for myeloid leukemia because analyses by timesince first exposure. . .(indicate) . . .highest risks within the first25 years”. But this statement is not literally correct as none ofthe three reports shows an actual increase in the risk of theMLs. The highest SMR ever reported for the MLs among formal-dehyde-exposed subjects in the NCI study is 95 (estimated fromdata in the second report). Thus the words ‘‘highest risks” in thequote should be replaced with ‘‘highest relative risks”.

The error of relying on RRs to describe exposure–response rela-tionships, in the absence of an overall SMR greater than 100, is wellknown. In fact, the error was pointed out in the context of the NCIcohort study by Marsh and Youk (2004). They re-analyzed the ori-ginal data of the second report and showed that the elevated RRsfor the MLs occurred because of statistically significant deficits ofdeaths in the referent categories. Beane Freeman et al. imply thatthe findings of Marsh and Youk are not relevant to the findingson the MLs in the third report because the non-exposed group inthis update showed an SMR of 65, a value not statistically signifi-cantly lower than 100. But the relevance of this SMR lies in the va-lue 65 itself, and not in its lack of statistical significance. In anycase, the highest RR for the MLs reported for peak exposure inthe third report is 1.8 (0.9–3.6). It is not statistically significant,is part of a trend that is not significant (p = 0.13), and when cor-rected for the referent group’s SMR of 65, would be about1.2(0.7–1.9).

The suggestion that the NCI cohort is positive for the MLs restsalmost entirely on the view that the supplement to the third re-port demonstrates an induction period of about 20 years for aformaldehyde–ML relationship. But, this finding is far too impre-cise to sustain a causal interpretation. Further, nearly 10,000 ex-posed subjects (46%) were still alive at the closing date of thethird report’s follow-up. National mortality statistics (CDC,2000) suggest that about 22 of these men will die from ML.Nearly all of these deaths will occur among men with a TSFEgreater than 30 years because all subjects were hired before1966 (Blair et al., 1986). This may extend upward the range ofTSFEs in which elevated RRs occur. Also, if just one or two addi-tional deaths occur in the referent group, the crucial RR of 2.4 willdecline sharply.

164 P. Cole et al. / Regulatory Toxicology and Pharmacology 58 (2010) 161–166

It is challenging to establish the induction period for a cancer inhuman beings. Those that are established have several characteris-tics: The exposure-disease relationship is recognized as causal. Insome studies the exposure occurred over a limited time. The dis-ease is uncommon. The number of subjects with relevant and accu-rate temporal information is large. The formaldehyde–MLrelationship shows none of these features except, perhaps, thatthe disease is uncommon. The representation that the NCI cohortstudy is positive and that it provides an estimate of the formalde-hyde–ML induction period, even in the absence of excess deathsfrom those diseases, stretches credulity.

Since 2004, four groups (Bachand et al., 2010; Bossetti et al.,2008; Collins and Lineker, 2004; Zhang et al., 2009) in additionto Marsh and Youk (2004) have reviewed or done meta-analysesof the formaldehyde–leukemia relationship. The studies included,and the modes of analysis used, differ among these reviews. How-ever, only one (Bachand et al., 2010) had access to the correctedand updated data reported by Beane Freeman et al. (2009). Threeof the four reviews found little or no evidence to support a formal-dehyde–leukemia association while the other (Zhang et al., 2009)supported an association with all leukemia and also with theMLs. This positive report relied heavily on the proportional mortal-ity studies underlying the embalmers study (Hauptmann et al.,2009) reviewed below.

3. The embalmers study

3.1. Background

In 2009 the NCI staff published an additional report (Haupt-mann et al., 2009) relating to formaldehyde and the LHCs. This re-search is unrelated to the industrial cohort study. Rather, itcombines and extends three proportional mortality ratio (PMR)studies published by the NCI from 1983 to 1990 (Hayes et al.,1990; Walrath and Fraumeni, 1983, 1984). Those studies used reg-istries, associations and licensing boards to identify 13,994 inactiveand deceased funeral directors and embalmers. The present studyis based on 6808 deaths that occurred from 1960 through 1985. Allor most of these decedents were included in the three earlier pub-lications. We refer to all subjects as ‘‘embalmers” and to the studyas the ‘‘embalmers study”.

Table 3Proportional Mortality Ratios according to disease group. Based on the data in theembalmers study by Hauptmann et al., 2009.

Disease group Estimated* number PMR** 95% conf. int.

All LHCs 143 90 (76–106)All myeloid leukemias 29 108 (70–156)Acute myeloid leukemia 20 116 (71–179)Nasopharyngeal cancer 4 128 (35–328)Brain tumors 44 120 (87–161)

* Total number, multiplied by the percent listed as the underlying cause: all LHCs(and myeloid leukemias), 85%. Nasopharyngeal cancer, 100%. Brain tumors, 92%.** The referent group (N = 852,003) is all white male decedents, aged 25+, USA,1979. Example: for the myeloid leukemias, there were 29 certified ML decedentsamong all 6808 embalmer decedents. The ML risk of death is 4.3/1000. The corre-sponding risk in the referent group is based on 3424 ML decedents and is 4.0/1000.The PMR is 4.3/4.0 = 108.

3.2. Subjects and interviews

Subjects were drawn from among the 6808 decedents and acase-control analysis is presented. Cases include 168 embalmerswhose death certificate had any mention of an LHC. Twenty-onecases, with rare forms of leukemia, were included only in the anal-yses for all LHCs. There also were four decedents with nasopharyn-geal cancer and 48 with ‘‘brain tumors”. Findings for these twodiseases were negative. Controls were 265 decedents whose deathcertificate made no mention of the cases’ diseases or of a few addi-tional conditions. Controls were frequency-matched to all LHC andbrain tumor subjects for source of identification, gender and datesof birth and death but were otherwise selected at random.

During 1990–1992, 1221 interviews were conducted with next-of-kin and co-workers of the subjects. The purpose of the inter-views and their methodology, (telephone, in person) are not de-scribed. The interviews were done four to 33 years after thesubjects’ deaths and up to 55 years after relevant employmenthad occurred. Forty-four percent of the ML cases began work be-fore 1932. The comparable figure for all controls was 27%. An inter-view was available from at least one next-of-kin for about 95% ofsubjects but no information is provided for co-workers or on par-ticipation rates.

3.3. Exposure assessment

There were many gaps in the exposure information obtainedfrom the interviews. An effort was made to link the interviewinformation to results of an exposure-assessment experiment(Stewart et al., 1992). A predictive model was developed to assignformaldehyde levels to embalming practices. Average levels offormaldehyde were thought to be assessed validly but the modelfor peak levels could not be validated.

Six indices of formaldehyde exposure were developed: (1) Yearsspent embalming. (2) Number of embalmings. (3) Cumulativeexposure. (4) Average formaldehyde level when embalming. (5)Time-weighted average formaldehyde level when embalming. (6)Peak level. The titles and descriptions of the indices suggest highcorrelation among them. This is borne out by the distribution ofsubjects over exposure levels of the six indices. Both for all LHCsand for the MLs, duration of embalming is the variable with thestrongest findings and the other variables appear to be derivedfrom or correlated with it. This is in contrast to the industrial co-hort study with diverse findings among the several exposureindices.

3.4. Proportional Mortality Ratios (PMRs)

We analyzed the embalmers study using PMRs in order tobring an external referent into the comparisons. The PMRs shownin our Table 3 include only decedents for whom the index diseasewas certified as the underlying cause of death. The comparisongroup is all U.S. white male decedents, aged 25+ in 1979 (CDC,1979). This year was selected because it probably is the medianyear of death in the embalmers study. A footnote to our Table 3provides an example of the method used to develop the PMRs.No PMR is meaningfully elevated and none approaches statisticalsignificance.

PMR studies are widely viewed as unreliable although this viewhas been challenged (Aveyard, 1998). We consider that selectionbias, the principal limitation of PMR studies, is absent or minimalin the embalmers study because of the geographic range (virtuallynationwide) and time span over which the embalmers beganworking (50 or more years).

3.5. Case-control analysis

These analyses begin with the stratification (dates of birth anddeath, smoking) that was used when the 265 controls were se-lected to correspond to the total 216 cases (LHCs and brain tu-mors). However, this correspondence does not persist when allcontrols are compared with the small subgroup of 34 cases of theMLs. Logistic regression was used to enhance the comparability

P. Cole et al. / Regulatory Toxicology and Pharmacology 58 (2010) 161–166 165

of cases and controls. These analyses adjusted for the stratificationvariables: year of birth, age at death, gender and smoking (ever vs.never). Results are presented as odds ratios (ORs) for successivelyhigher formaldehyde exposure levels within each of the six indices.Trend tests also are presented.

For all 168 LHCs combined, only one of the six trend tests, thatfor duration of embalming, approached statistical significance(p = 0.06). For LHCs of lymphoid origin (N = 99), five of the sixexposure–response relationships were slightly inverse and therewas no association with formaldehyde. For MM, the only OR pre-sented was 1.4(0.4–5.6) for ever vs. never embalming. For theHLs (N = 8) the OR was 0.5(0.1–2.6) for the same exposure index.Both MM and HL were suggested to be associated with formalde-hyde, perhaps causally, in the industrial cohort study (Beane Free-man et al., 2009) described above. For LHCs of non-lymphoid origin(N = 48) the six exposure–response relationships were weak withstatistical significance approached only for one, again duration ofembalming (p = 0.05).

Thirty-four cases in the non-lymphoid group are MLs, the focusof the embalmers study. Compared to the controls these 34 MLcases were born and died earlier. They began work in a funeralhome when 4.3 years younger than controls. They also beganworking earlier, perhaps much earlier, in calendar time. More cases(88%) than controls (78%) were ever-smokers.

The six analyses were done twice for the MLs. The first analysesused a referent group (‘‘never” embalmed) with only one case and55 controls. These analyses produced implausibly high ORs with 12of the 18 values being greater than 10. Two of the six trend tests,those for duration of embalming (p = 0.02) and for peak formalde-hyde level (p = 0.04), were statistically significant but only whenthe referent group was included in the analysis. The embalmers re-port indicates, and we agree, that the results of the second set ofanalyses, with five cases and 88 controls in the referent group(‘‘<500 embalmings”), ‘‘. . .represent more conservative but proba-bly more reliable risk estimates for high-level exposure. . .”, thandoes the first set. In these second analyses, the average of the 18ORs for exposed subjects was 2.4 and none was greater than 3.9.Surprisingly, this second and more defensible set of analyses wasnot evaluated for statistical significance. Without explanation orprecedent, the p-values from the first set of analyses are attachedto the results of the second set. Thus, the most reliable data relat-ing to the MLs in the embalmers study were not assessed for sta-tistical significance. In reviewing the six patterns of ORs in themore reliable data, we note minimal trends among exposedsubjects.

In sum, despite some evidence of a formaldehyde–ML associa-tion in the embalmers study, there is little evidence of exposure–response relationships. The effects of the cases’ earlier (in calendartime and age) employment are unknown but may have resulted inmore embalmings, higher peak exposure, etc. The ever–never con-trol of cigarette smoking may not have been adequate to eliminatethe effect of the causal association between smoking and the MLs.

Data are presented for acute myeloid leukemia (AML, N = 20),the largest subset of the MLs and the only form of ML known tobe caused by chemical exposure. One of the six trend tests donefor AML, that for peak exposure, was statistically significant(p = 0.04) among all subjects. However, two observations counterthe view that formaldehyde actually is associated with AML and,as a practical matter, with the MLs collectively. First, the adjustedORs presented in the embalmers study for the MLs are very similarto those that can be calculated directly from the crude data. Wesubtracted the data for AMLs from those for all MLs and calculatedORs for the residual disease (in effect, chronic myeloid leukemia).The ORs for AML and for ‘‘other MLs” are virtually identical. Sec-ond, among the embalmers, AML decedents make up 59% of allML decedents, virtually identical to the corresponding 63% in na-

tional data (CDC, 2000). In short, if there is an association of form-aldehyde with the MLs in the embalmers study, it is not specific toeither of the two major forms of ML.

3.6. Interpretation

The PMRs in the three underlying studies of embalmers sug-gested a weak association between formaldehyde and the MLs.For the embalmers study to add support to that association itwould have to provide persuasive evidence of exposure–responserelationships for specific exposure indices. The embalmers studyconcludes that, ‘‘formaldehyde exposures in the funeral industrywere associated with statistically significant increased risk formortality from myeloid leukemia”. The statement rests on two sta-tistically significant trends seen in unreliable data and three stra-tum-specific risk estimates of borderline statistical significance.

In contrast to the quote above, there is no ‘‘increased risk” of MLmortality presented in the embalmers study as the only data pro-vided are relative risk estimates. The PMR of 108 for the MLs, esti-mated by us, suggests that there is little or no actual, or absolute,increased risk. Further, while two of the six trend analyses forthe MLs are significantly positive, that is so only when the non-ex-posed are included. Most problematic is the fact that while a largenumber of analyses and p-values are presented, the most reliabledata have not been tested for statistical significance.

We suggest that there are two analyses that could be done toenhance the embalmers study. First, since the positive interpreta-tion of findings relating to the MLs in the industrial cohort studyrelies on an association of the MLs with time since first exposureto formaldehyde, the embalmers study should be evaluatedsimilarly.

A second analysis would be based on variable-ratio matched-sets of cases and controls. Since there are 265 controls there shouldbe available at least two controls for each of the 34 ML cases andthree or four controls for some. While matching for duration ofemployment runs the risk of over-matching, it should be done todetermine whether any association with number of embalmingsor cumulative exposure to formaldehyde persists.

4. Assessment

The two studies reviewed differ in their findings for multiplemyeloma and the Hodgkin lymphomas – the cohort study is repre-sented as positive and the embalmers study as negative. Althoughcomparisons of results from the two studies for identical exposuresare not possible, a reasonable comparison can be made for cumu-lative exposure and the MLs. Among industrial workers with thehighest cumulative exposure to formaldehyde (5.5+ ppm-years)the RR is 1.0(0.5–2.2). Corresponding figures for the embalmersare about 4.5 ppm-years and an OR of 3.1(1.0–9.6). Thus the twostudies are not close to agreement on this comparison.

Individually and combined, the two studies reviewed do notsupport a causal relationship between formaldehyde exposureand death from the LHCs including the MLs. Neither study demon-strates an actual increased risk of any LHC among workers withmoderate to heavy exposure to formaldehyde and neither studypresents reliable and statistically significant evidence of any expo-sure–response relationship. Lu et al. (Lu et al., 2010) recentlyshowed that endogenously-produced formaldehyde forms DNAadducts, DNA-DNA cross links and DNA-protein cross links inmany, and possibly all, rat tissues. However, exogenous formalde-hyde forms adducts and cross-links only in the nasal mucosa.Exogenous formaldehyde cannot form adducts or cross-links atsites remote from the portal of entry such as the bone marrowand the peripheral blood. The paper itself and an editorial thataccompanied it (Lehman-McKeeman, 2010) stated that, ‘‘In their

166 P. Cole et al. / Regulatory Toxicology and Pharmacology 58 (2010) 161–166

totality, the data from Lu et al. suggest that inhaled formaldehydeis unlikely to cause leukemia.

Acknowledgment

Funded in part by a grant from the Formaldehyde Council.

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