1 

DATE: April 13, 2010 

SUBJECT: REVIEW OF US ENVIRONMENTAL PROTECTION AGENCY’S 

DRAFT FORMALDEHYDE ASSESSMENT 

Submitted by : NCEH/ATSDR 

The review of the literature seems adequate and completely covers the issues in the draft 

document. Specifically, Volume I of IV includes the critical studies relevant to the topic and the 

studies are presented with much detail. Volumes II and III of IV provide a very comprehensive 

review of the toxicological, genotoxic, carcinogenic effects, and risk assessment of 

formaldehyde. 

Comments on Volume I 

Specific comments are as follows: 

• Page 2-1, line 29 – Please delete extra comma. 

• Page 2-2, Table 2-1 – Please spell out CASRN to be consistent with rest of 

table. 

• Page 2-3, line 3 and page 2-11, line 35 – The use of suntan lotion may be a bit 

confusing. Suggest changing to sunscreen to avoid confusion with tanning 

lotion. 

• Page 2-3, line 2-6 – States that formaldehyde is used in a list of cosmetic 

products, however, pages 2-11 and 2-12 state that these cosmetic products 

contain formaldehyde releasing agents, but not actually formaldehyde. 

Suggest using consistent wording. 

• Page 3-3: line 12 – Please delete a) line 14 - delete colon at end of sentence 

and replace with period; line 19-add comma after pool. 
2 

• Page 3-3, last paragraph – Choose another numbering format (such as “a” and 

“b”) within this paragraph since i and ii are already used in the first numbering 

format of this section. 

• Page 3-23, lines 5-6 – Specify which species this sentence is referring to. 

• Page 3-28 line 22 and 27 – Insert 2005 after Moser et al. 

• Page 3-33, line 12 – Delete the duplicate human respiratory tract. 

• Page 3-33, lines 26-27 – Delete unnecessary parentheses. 

Comments on Volume II

The volume was very lengthy and somewhat tedious to read, primarily because in Sections 4.1 

through 4.3, each study was described in extreme detail regardless of the quality of the study or 

its relevance to risk assessment. The numerous summaries of the data given at the end of 

subsections were very helpful. Nevertheless, the volume didn’t give any synthesis and 

evaluation of the data until Section 4.4, 370 pages into the text. It may be helpful to condense 

the information. 

Specific comments are as follows:

• Inconsistent units are used i.e., parts per million (ppm); parts per billion 

(ppb); milligrams/cubic meter (mg/m3); and micrograms/cubic meter 

(μg/m3). 

• Page 4-2, line 28: Pease change 392 to 397. 

• Page 4-2, lines 34 and 35: Measurements of formaldehyde exposure were 

taken from two rooms of the home, usually the bedroom and living room, 

and the samples were kept..... 

• Page 4-3, line 5: Change increase to increased. 

• Page 4-3, line 29: Change geometric mean to median concentration 

• Page 4-4, line 14: “(65% mobile homes, 27% conventional homes, 2% 

travel trailers, 2% office buildings, etc).”

• Page 4-5, line 29: A Swedish study conducted at a chemical plant found that

nasal and eye discomfort were 

• Page 4-8, line 12: The 0.25 mg/m3 concentration is incorrectly converted to 

308 ppb. It should be 0.203 ppm or 203 ppb. 
3 

• Page 4-18, line 15: change All four reports to All five reports 

• Page 4-21, line 8: Do not offer information on the concentrations at which 

adverse effects would be expected in a...

• Page 4-23, line 11: Change “they did report at increased risk” to “they did 

report an increased risk.” 

• Page 4-23, line 16: A study performed by Tuthill (1984) measured 

formaldehyde in the homes of exposure for children 

• Page 4-24, line 28: Change “gender to and odds ratio” to “gender to an odds 

ratio.” 

• Page 4-25, line 26: Change “were” to “of”. 

• Page 4-26, lines 28-34: The statement that starts on line 33 “This small study 

reported only incidence of lesions and did not score based on severity of 

lesions” is confusing because scores are provided in the previous text 

description (see lines 28 ...) with such words as (with an average severity 

score of 2.3). Suggest deleting the highlighted sentence. 

• Page 4-27, lines 3-4: Holmström et al. (1989) collected nasal biopsy samples 

from workers not exposed to formaldehyde and 70 workers exposed air or to 

formaldehyde at a median concentration of 240 ppm ppb. (See p 4-17 line 

19, concentration is correctly reported as 0.240 ppm (240 ppb). 

• Page 4-28, line 29: What is SI-induced? This term is not defined or 

mentioned elsewhere in the volume. 

• Page 4-29 line 4: Change “median” to “mean”. 

• Page 4-30, line 35: Change “value” to “values”. 

• Page 4-31, line 1: of formaldehyde in the application of carbamideformaldehyde glue was found to be 0.71 ppm TWA...

• Page 4-38, line 32-34: Blood serum albumin (HSA) samples were 

collected and assayed for IgE and IgG activity against formaldehyde. None 

of the workers had IgG activity against formaldehyde. Five workers had 

comparable IgE activity against both formaldehyde HSA and HSA that was more 

than twice the normal control serum levels. No IgE antibodies were 

detected in the other 32 workers. (See write-up on p 4-40.) 
4 

• Page 4-57, line 29: Change “4.1.2.1.1. NPC” to “4.1.2.1.1. Nasopharyngeal 

Cancer (NCP)”

• Page 4-59, Table 4-1: Please make the tabular entry clear that Hauptmann et 

al. (2004) study is the NCI cohort. 

• Page 4-72, Table 4-2: For the Luce et al., 1993 entry, it is not clear what the 

average levels of ≤2 and ≥2 represent– are they concentrations? Or are they 

low (1-3) as defined by Luce et al.? 

• Page 4-73, Table 4-2: For the Hayes et al. entry exposure levels in the 

Exposure Assessment column are expressed as low (<0.0 ppm) [what does 

this mean?], medium (0.1-1 ppm); and high (>1 ppm), but in the Results... 

column, the levels are given as ≤2 and ≥2. Why the discrepancies. 

• Page 4-76, 4.1.2.1.3: The paragraph is very confusing. On line 35, it says 

(see Table 4-3), but the studies to which this refers are not entered in Table 4-

3. Nor are the subsequently cited industrial worker cohorts where buccalpharynx cancer was examined in Table 4-3. The studies that appear in Table 

4-3 are discussed starting in the last of page 4-77. 

• Page 4-84, line 16: Change “4.1.2.2.1. LHP cancers” to “4.1.2.2.1 

Lymphohematopoietic (LHP) cancers”

• Page 4-85, line 5: Delete “and laboratory technicians”. 

• Page 4-88, line 3: The PMR for myeloid leukemia is given as 1.61 [95% CI: 

1.02-2.41] on p 4-88 but as 1.57 [95% CI: 1.01-2.34] on Table 4-4, p 4-105. 

The data for other leukemia is also missing from Table 4-4. 

• Page 4-93, lines 14-22: It is not clear whether these data refer to the Stayner 

study or to the update by Pinkerton. 

• Page 4-95, line 14: Says that formaldehyde levels ranged from 0.1 to 1.0 

mg/m3

, but the entry in Table 4-4 on p 4-104 reports 1-5 μg/m3. 

• Page 4-95, line 16 and 17: The text says there were 2 (1.0 expected) 

lymphomas, and 2 (0.5 expected) multiple myelomas, yet the tabular entry 

reports these as SMRs of 1 and 4. This entry in Table 4-4 is misleading. 

• Page 4-95, lines 21-35: Why is the Dell and Teta (1995) study even 

discussed? It seems to be more about benzene and toluene. Nowhere in the 

description of the study does it say there was formaldehyde exposure. 

• Page 4-96. Section 4.1.2.2.1.3 is titled Summary of non-respiratory tract 
5 

cancers and then is followed by Sections 4.1.2.2.2 and 4.1.2.2.3, which are 

discussions of brain and CNS cancer and pancreatic and other cancer. Aren’t 

these also non-respiratory tract cancers? Perhaps the summary should follow 

these subsections on p 4-107. 

• Page 4-98, Table 4-4: For the Harrington and Shannon entry, the study 

design column should indicate that there are 12,944 laboratory technicians. 

The 2,079 number is just for the pathologist and is not inclusive of laboratory 

technicians. 

• Page 4-99 Table 4-4: For the Luce et al. entry the cohort consisted of 5,485 

pathologists, not 4,485. 

• Page 4-102, Table 4-4: The Pinkerton et al. entry should make it clear that it 

is an update of the Stayner et al study. 

• Page 4-103, Table 4-4: The Coggon et al. entry should make it clear that it is 

an update of the Gardner et al. study. 

• Page 4-103, Table 4-4, For the Bertazzi et al entry, indicate the exposure 

levels were 0.16 to 3.1 ppm. 

• Pagev 4-110, 4.2.1 Noncancer Health Effects: This title is misleading 

because cancer effects appear here also (see also page II-v – Contents – 

misleading). It should be renamed Non cancer and Cancer effects. 

• Page 4-131, lines 22-27: Inconsistent referencing to exposure levels 145 

ppm vs.145.6 ppm. There are other instances in the document where this 

occurs; suggest global checking. 

• Page 4-144, Table 4-15: Fill in the empty boxes in the column for 

extra-pulmonary effects. 

• Page 4-148, Table 4-17: Indicate in the title that there were 10 male and 10 

female rats examined, otherwise the number of animals with the effects is 

unclear. 

• Page 4-169, lines 22 and onward: Suggest presenting the data for 

formaldehyde alone rather than formaldehyde and HCl. 

• Page 4-205, line 20 and 21: Johannsen et al. (1986) performed a subchronic 

study by using rats and dogs exposed to paraformaldehyde dissolved in 

drinking water and dogs exposed to formaldehyde in the diet.

• Page 4-206, line 17: This says that the study suggest a NOAEL of 150 

mg/kg/day. There was decreased weight gain. 
6 

• Page 4-217, lines12 and 13: Sub chronic exposures at 61 and 99 ppm 

formaldehyde would be expected to result in frank toxic effects in mice (see 

Section 4.2.1). The study (Leach et al 1983) was conducted in rats, not mice. 

Would frank effects at 61 and 99 ppm be expected to in rats? 

• Page 4-225, line 26: Change “systematic” to “systemic”. 

• Page 4-227, line 8: One form of sensitivity directly affects sensory nerve... 

Is there a word missing between the two commas? 

• Page 4-288, lines 4: The Kilburn and Moro (1985) study was available only 

in abstract and was not found as a subsequent published article. Why include 

it? If the abstract appeared 25 years ago and was never published, maybe it 

was rejected or the authors withdrew it. 

• Page 4-288, line 14 to p 4-290, line 16: Why include these studies by 

Gofmekler and Bonachevskaya, 1969, Gofmekler 1968, and Pushkina et al 

1968 if they are so flawed. The extensive detail descriptions, including the 

tabular data is somewhat distracting and adds to the length and tedium; 

suggest condensing the discussion. They are even included in Table 4-69, 

where levels of 0.01 and 0.08 ppm are identified as LOAELs for 

developmental effects. This is somewhat misleading in that a LOAEL of 5 

ppm is identified on p 4-309, line 17 from the Martin study (See below). 

• Page 4-290, line 32: Sanotskii et al 1976 is cited parenthetically. Is it cited 

anywhere else in the document? 

• Page 4-295, line 19: Another abstract is cited. 

• Page 4-309, line 17: The LOAEL for developmental effects in rats is 5 ppm. 

ATSDR’s Toxicological Profile did not give much credence to the 5 ppm 

level as LOAEL in the Martin 1990 study. Neither did Martin. It is further 

misleading, because much lower LOAELs are identified in Table 4-69. For 

example, 0.01 and 0.08 are identified as LOAELs in Table 4-69 for the 

Gofmekler studies and 0.41 ppm in the Senichenkova studies. As noted in 

General Comments, this is kind of reporting that each study was described in 

extreme detail regardless of the quality of the study or its relevance to risk 

assessment. 

• Page 4-317, Table 4-70: Suggest reporting the Hurni and Ohder (1973) ppm 

dietary concentrations as mg/kg/day as was done in the text. The 

concentrations of formaldehyde in the chow were 0, 125, or 375 ppm, 

equivalent to doses of 0, 3.1, or 6 9.4 mg/kg-day, respectively. 
7 

• Page 4-324, line 2: Change “chronicle” to “report” Chronicle means to 

record in chronological order or to make a historical record. 

• Page 4-324, line 34: 10 ppm should be 15 ppm. 

• Page 4-330, line 13: 10 ppm should be 15 ppm. 

• Page 4-330, line 22: Swenberg et al (1983) should be Swenberg et al (1980). 

• Page 4-345, lines 14 and 15: “...Speit et al. (2000) it has been have shown 

that formaldehyde causes DNA repair inhibition at a concentration range of 

0.125 mM to 10 mM). 

• Page 4-345, line 17: Change “followed” to “followed”. 

• Page 4-353, line 20: 4.3.3.2. Mutagenicity in Other Non-Mammalian 

Cell Systems. 

• Page 4-404, line 10: The use of mosquito coils in the Philippines (West et al. 

1993). This has not been discussed anywhere else in Volume II. 

• Page 4-411, line 8: Bosetti et al., (2008) has not been discussed previously in 

Volume II. 

• Page 4-429, line 14: Change “calstogenicity” to “clastogenicity”. 

• Page 4-432, line 24: Altered ciliary beat has been noted in as little as 15...

Comments on Volume III

1. Rumchev et al., (2002)

• Under Alternative A page 5-69 of US EPA’s Draft Assessment of 

Formaldehyde, EPA proposed to use an uncertainty factor (UF) of 3 

for human variability, and also to use an UF of 3 for extrapolation 

from sub-chronic to chronic exposure, and apply these UFs to a No 

Observed Adverse Effect Level (NOAEL) of 33 parts per billion 

(ppb), which was based on results from Rumchev, et al., (2002) to 

derive at a chronic Reference Concentration (RfC) of 3.3 ppb for 

chronic inhalation exposure to formaldehyde. 

• In the Rumchev et al., (2002) study, the formaldehyde/asthma 

hypothesis was investigated in young children whose ages ranged from 

6 months to 3 years old. 
8 

• Children of those ages have developing immune and enzymes systems, 

and developing central nervous systems. 

• Nitrogen dioxide, volatile organics, dust mite, and PM 10 particles 

were also detected in air samples from the homes investigated in the 

Rumchev et al., (2002) study. 

• The investigators in Rumchev et al., (2002) indicated that their 

equation model showed that children in the study exposed to 

formaldehyde air levels exceeding 49 ppb were at increased risk of an 

incidence of asthma. 

• However, there was no indication of any adjustments made for 

 co-exposure to formaldehyde, and the other contaminants reported 

 in that study i.e., nitrogen dioxide, volatile organics, dust mite or PM 

 10 particles. 

• Therefore, the effects observed in the young children in that study may 

have been as a result of exposure to formaldehyde, or from 

 co-exposure to formaldehyde and other indoor air contaminants. 

• Moreover, difficulties in differentiating wheezing , because the 

children in the investigation were so young, may have provided 

confounding variables in the study; and the questionnaires employed 

in the study were filled out by the parents of those children months 

after the occurrences of the asthmatic symptoms. 

• Therefore, because of undeveloped enzyme and immune systems in 

the young children examined in the Rumchev et al., (2002) study, the 

children may have been especially vulnerable to toxic insults of indoor 

air contaminants or to co-exposure to indoor air contaminants, and 

could be considered a sensitive population. 
9 

• Why use an UF of 3 for human variability if a sensitive population was 

present? 

2. Garrett et al., (1999)

• Under Alternative A page 5-51 of US EPA’S Draft Assessment of 

Formaldehyde, EPA proposed to calculate an RfC of 2.8 ppb for 

chronic inhalation exposure to formaldehyde by applying an UF of 3 

for extrapolation of a Lowest Observable Adverse Effect Level 

(LOAEL) to a NOAEL, and applying another UF of 3 for human 

variability to a LOAEL of 28 ppb, which was derived from the results 

of the Garrett et al., (1999) study. 

• EPA’s justification for using the UF of 3 for human variability is that 

“since the study findings controlled for both parental asthma and 

family history it was unclear whether the effects observed in the 

children were from a sensitive population.” 

• Garrett et al., (1999) indicated that an apparent association between 

asthma in children and formaldehyde exposure existed, but the 

“association did not remain after adjustments were made for parental 

allergy and parental asthma i.e., the odds ratio for asthma in children 

was not significantly different from 1.” 

• The LOAEL probably should have been considered a NOAEL based 

upon the lack of statistical significance of an adverse effect when an 

adjustment was made for parental allergy and parental asthma. 

• If it was an actual LOAEL (28 ppb), then the population on which the 

LOAEL is based is the most sensitive population and any adjustment 

for sensitivity may be inappropriate. 

• The effects were based on recall over a year period. It is possible that 

the reported symptoms did not actually occur within the one-year 

study period. In addition, positive responses may have been reported 

merely because a child had an allergy or asthmatic problems in the 

past, and the parents wanted this recognized. 

• The presence of airborne chemicals other than formaldehyde and NOx 

were not tested. Oven cleaners, bleach, ammonia, and other household 

chemicals such as paints or solvents can cause asthma-like symptoms. 

Furthermore, asthmatics are often sensitive to other odors, such as 

perfume and deodorants. Moreover, emotional stress (with or without 

the presence of airborne chemicals) can sometimes elicit an asthmatic 

event. 

• Although 33% of the children were reported to be exposed to passive 

smoking, there were no adjustments for passive smoking indicated. 
10 

• Heavy smoking (especially in cars) can elicit asthma attacks or other 

symptoms of respiratory distress. 

• Since samples were collected only four times, additional uncertainty 

may have been created. 

• The actual exposure level was not known at the time the reported 

asthma or asthma-like events were experienced (i.e. proximity to the 4 

monitoring sessions is unknown). 

• Although tests for environmental particles such as pollen and mold 

were conducted, it is unclear what the precise cause of any reported 

asthma-like symptoms was. 

• This may be a possible cause of the onset of symptoms in the study 

population, although it was apparently not considered or even known 

to the researchers. 

• The study population may have been biased, since there was a larger 

number of respondents to the study solicitation by parents with 

asthmatic children. 

• To the best of our knowledge, the hypothesis that exposure to indoor 

air levels of formaldehyde enhances asthmatic episodes to allergens 

has not been reported by results from a controlled environment, until 

recently. 

• For example, Ezratty et al., (2006) exposed 12 subjects between 18 

and 44 years of age to 400 ppb of formaldehyde, or to pure air, in a 

controlled study for 60 minutes on 2 different days at 0700 hr. 

• The formaldehyde exposures were on the same day of the week, and 

separated by 2 weeks between. 

• The objective of the Ezratty et al., (2006) study was to ascertain 

whether a 1 hour exposure to 400 ppb of formaldehyde enhances the 

asthmatic responses to inhaled pollen allergen in volunteers who were 

reported to have pre-existing intermittent asthma. 

• The investigators in Ezratty et al., (2006) concluded that inhalation 

exposure to 400 ppb of formaldehyde did not enhance the asthmatic 

response to allergen, and that an underlying protective effect was 

observed. 

• These investigators also indicated that “additional studies with 

repeated exposures to formaldehyde are necessary to clarify the 

interactions of formaldehyde and allergens in the airways of subjects 

with pre-existing asthma” (Ezratty et al., 2006). 

• However, a recently published meta-analysis study has provided 

support for the formaldehyde inhalation exposure/asthma hypothesis 

(McGwin et al., 2010). 
11 

• Under Alternative B on page 5-52 of US EPA’S Draft Assessment of 

Formaldehyde, EPA indicated that Figure 5-8 refers to formaldehyde 

levels related to increased incidences of asthma from the Garrett et al., 

(1999) study, but Figure 5-8 depicts prevalence of eye irritation from 

the Ritchie and Lehnen (1987) study (See figure 5-8). 

• Please make units consistent in Tables with those in the Text, e.g. 

make all units parts per billion, or micrograms/cubic meter for clarity 

(See pages 5-48; 5-51; 5-53 and 5-54). 

3. Ritchie and Lehnen, (1987)

• Under Alternative A page 5-59 of US EPA’s Draft Assessment of 

Formaldehyde, EPA proposed to apply an UF of 3 (human variability) 

to a NOAEL of 50 ppb to derive at an RfC of 17 ppb for chronic 

inhalation exposure to formaldehyde. 

• EPA indicated that the basis for using the UF of 3 for human 

variability was because of “prevalence rates decreasing the likelihood 

that effects on sensitive individuals would be lost due to response 

averaging.” 

• The subjects in the Ritchie and Lehnen (1987) study were less than 7 

years of age and up to 54 years of age in both sexes. 

• According to Ritchie and Lehnen (1987), “subjects exposed to 

formaldehyde in the Hanrahan (1984) study showed a dose response 

relationship for burning eyes and eye irritation, and age had an inverse 

relationship with burning eyes and eye irritation in that study.” 

• However, negative effects of age for the eye irritation response were 

not reported by data from the Ritchie and Lehnen (1987) study. 

• Nose and throat irritation data for respondents under the age of 7 were 

not used in the Ritchie and Lehnen (1987) study. 

• Furthermore, there was no indication in the Ritchie and Lehnen study 

that respondents under age 7 eye irritation data were used; 

• Therefore, the study does not appear to have made adjustment for age 

in the model. 

• The effects observed may have been driven by children under 7 years 

of age, and if so, an UF should not be used. 

• By contrast, if it can be determined that the adverse effects observed in 

the Ritchie and Lehnen (1987) study were driven by a group that is 

over 7 years of age, then it would be prudent public practice to act 

conservatively and apply an UF of 3 for human variability. 
12 

• Alternative A page 5-59 of US EPA’S Draft Assessment of 

Formaldehyde, EPA stated that the prevalence rate in the less than 100 

ppb exposure to the formaldehyde group from the Ritchie and Lehnen 

(1987) study was 1 to 4%. 

• However, on page 324 of Ritchie and Lehnen (1987) study under the 

eye irritation section it depicts that at less than 100 ppb of 

formaldehyde exposure there was approximately 1 to 2% of the 

subjects reported eye irritation. 

• Although there was no information provided to indicate what age 

group was mostly responsible for the adverse irritation effects in the 

Ritchie and Lehnen study, it seems as though a sensitive subpopulation may have been incorporated, since the subjects in the study 

ranged from less than 7 years of age with developing enzyme, immune 

and central nervous systems, to 54 years of age of both sexes. 

• Why use an UF of 3 for human variability since a sensitive subpopulation in the Ritchie and Lehnen (1987) study may have been 

present? 

4. Taskinen et al., (1999)

• The final group of women in the Taskinen et al., (1999) study as 

shown in Table I consisted of 602 women. From this group there were 

drawn unexposed and exposed individuals. Whereas for the 

Formaldehyde and Phenols variables the total number of exposed and 

unexposed was 602. 

• The sum of the unexposed and exposed for Organic Solvents, Dusts 

and Wood dusts variables was 630. 

• Where did these 28 individuals come from? 

• Are they the 28 cases where the time-to-pregnancy (TTP) period had 

started before entering the branch (page 211 lines 19-20) of the 

Taskinen et al. study? 

• Were these 28 cases included in the analysis of TTP and Organic 

Solvents, or Dust or Wood dust? 

• If this is a typographic error, in which categories where the number 

over represented? 

• Exposure Assessment. From Table II there were 114 out of 235 

women, roughly 49% of the exposed women, where no data of 

formaldehyde measurements were available. 

• However, for exposure assessment, “measurement from workplaces of 

the same industrial activity were used as the basis of estimation” (page 

208). 
13 

• Are there studies that show a good correlation on exposure 

measurements between workplaces with same industrial activities? 

• Could it be that the measurements used may have overestimated as 

well as underestimated the exposure measurements, and thus 

weakened the conclusion of the study? 

• Has the data been analyzed using only women from workplaces where 

the measurements were done? 

• If this the case, have the results been different in term of statistical 

significance? 

• Recall Bias. In the calculation of the Daily Index, the proportion of the 

exposed work time during a work-data depends on the detailed work 

task description from the questionnaires. 

• In this case, might the recall bias have been a problem? 

• Regarding the Fecundability Density Ratio (FDR). The odds ratios 

for formaldehyde were, as for Table VI page 209, adjusted for the 

following potential confounding factors: employment (yes/no); 

smoking; alcohol consumption, irregular menstrual cycles and, number 

of children. 

• The aOR was significant for the high formaldehyde-exposed group 

(aOR 0.64; 95%CI=0.43-0.93). 

• At page 210, first paragraph, it seems also that when phenols were 

entered in the model the aOR strengthened (aOR=0.57; 95%CI=0.37-

0.85) and we are assuming that it refers to the formaldehyde-exposed 

group versus non-exposed group, since it did not mention that the 

categorical variable formaldehyde was used as four groups 

(high/medium/low/unexposed). 

• In this case, the number of observations that were calculated in the 

model should have been lower than the previous one, since "all women 

exposed to phenols (n=68 from Table VIII and in the text) were also 

exposed to formaldehyde, but not vice versa.” 

• In the introduction section of the Taskinen (1999) paper, page 207, it 

is stated and given references that occupational exposures to organic 

solvents have been related to several reproductive effects, among them 

reduced fertility and spontaneous abortions that are health outcome 

variables in the investigation. 

• In the Taskinen (1999) study, exposure to organic solvents was not 

associated with Fecundability Density Ratio and we note that in the 

model was also included formaldehyde. 

• In this case the categorical variable formaldehyde entered as two 

groups (exposed/unexposed) or four groups (high/medium/low/ 

unexposed). 

• In the latter case, what were the aOR for the different formaldehydeexposed groups? 
14 

• That is, when in the model were included formaldehyde and organic 

solvents was the aOR for formaldehyde still statistical significant, and 

what was the magnitude of any change? 

• Since the rational to adjust the OR for organic solvents with the 

inclusion of formaldehyde would have been the fact that formaldehyde 

have been reported to be somewhat associate with prolonged time to 

pregnancy, this is also true for the organic solvents and therefore 

should have been a confounding variable in the model for FDR and 

formaldehyde exposure. 

• Regarding the Previous Spontaneous Abortion Outcome. It is not 

clear whether the previous spontaneous abortion reported by women 

has been previously diagnosed by a doctor or self-diagnosed. 

• However, there were 96 women reporting spontaneous abortions, and 

of this, 52 women had the same work place during the year of 

spontaneous abortions as they had during the beginning of the time-topregnancy. 

• The analysis restricted only to these 52 women reported a significant 

OR to have had a spontaneous abortion. 

• Although it is not specified on page 210 of the Taskinen (1999) paper 

what type exposure, except that there were three groups 

(high/medium/and low). 

• We may assume that it was formaldehyde since the abstract stated that 

“Additionally, an association was observed between exposure to 

formaldehyde and an increased risk of spontaneous abortion..” 

• In the last sentence of the method section is stated that: “The odds 

ratios (OR) for other outcomes were calculated by unconditional 

logistic regression: adjustments were done for age, employment, 

smoking and alcohol consumption.” 

• So, is it correct to assume that the OR for spontaneous abortion was 

adjusted only by these confounding factors? 

• Among these 52 women, there were women with endometriosis, since 

their endometriosis has been associated with spontaneous abortions? 

• Among these 52 women, there was also reported exposure to organic 

solvents (a variable that has been previously associated with 

spontaneous abortions, as stated in the introduction, and therefore 

could have been a risk factor)? 

• If there were organic solvent exposures, would the inclusion of this 

variable in the model have altered the statistical significance of the 

formaldehyde exposure? 

• There was also no mention of this important finding in the discussion 

section, or in the conclusion section, whereas several paragraphs are 

spent discussing the endometriosis and salpingo-oophoritis results. 

• Yet these finding found relevance in the abstract. One wonders 

whether the authors were unsure about the spontaneous abortion 

finding. 
15 

• Regarding the Endometriosis Outcome. 

• Is the OR for organic solvents adjusted also for formaldehyde? 

• If so, what would have been the OR for each formaldehyde-exposed 

group? 

5. ATSDR’s Toxicological Profile on Formaldehyde

• ATSDR is currently re-evaluating the chronic inhalation exposure 

Minimal Risk Level of 8 ppb for formaldehyde through the 

development of a Toxicological Profile for Formaldehyde. 

• The agency will soon release an updated literature review for 

formaldehyde. 

• Finally, ATSDR does not refute or cast doubt upon the Hauptman et 

al. (2004) epidemiological study, which provided results of increased 

risks of formaldehyde induced nasopharnyxgeal cancer in former 

workers from 10 US formaldehyde related plants. Reportedly, the 

National Cancer Institute derivation of its carcinogenic classification 

of formaldehyde was based on the results of the Hauptman et al. 

(2004) epidemiological study. ATSDR suggests to approach and to 

evaluate the results of the Hauptman et al., (2004) study with caution. 

This is based upon our knowledge of independent reviews of the 

epidemiological data by other authors who previously have casted 

doubt on the Hauptman et al. (2004) study i.e., Marsh et al., (2007) 

and Bosetti et al., (2006). 
16 

REFERENCES 

C. Bosetti, J. K. Mc Laughin,R.E. Tarone, E. Pira, and C. La Vecchia. Formaldehyde and cancer 

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