688 R. Golden of the most sensitive effects related to acute formalde- hyde exposure based on a pooled analysis of 11 published controlled human studies (including healthy individuals and asthmatics). Parameters evaluated included concen- tration range (i.e., 0 to <0.3 ppm; 0.3 to <0.75 ppm; 0.75 to <1 ppm; 1 to <2 ppm; 2 to <3 ppm;.>3 ppm), site of the irritating effect (i.e., eye, nose, or throat), and degree of severity of the effect (baseline [effect in the absence of formaldehyde exposure], mild effects, moderate effects, and severe effects). As concluded by Noisel et al. (2007), “The experimental data show that there was no differ- ence in the proportion of individuals experiencing effects between the control group without occupational exposure and groups exposed to formaldehyde concentrations under 0.75 ppm. For this reason, the theoretical percentage of response attributable to formaldehyde exposure was con- sidered to be zero for the moderate effects on the eyes, nose and throat for all the concentrations below 0.75 ppm…. According to our analysis of the defined exposure–response relationship, at concentrations below 0.75 ppm, there is thus little probability for formaldehyde-induced irritation to occur...” This analysis was conducted by considering formaldehyde exposure alone and not mixed-exposure situations such as in occupational settings where form- aldehyde is used and where other chemical substances (e.g., phenol, sodium hydroxide, etc.) and dusts (e.g., wood or paper dust) may also be present with irritating effects of their own. The US EPA (US EPA/NCEA, 2005) conducted a quan- titative analysis of controlled human exposure data to derive human health effects criteria for formaldehyde. Response data from six human volunteer studies com- prising 250 observations and reported symptoms were categorized into the four numerical descriptors and symptoms: (0) no effect noted or reported; (1) mild signs and symptoms: irritation noticed, but not considered annoying; (2) moderate signs and symptoms: irritation annoying; and (3) severe signs and symptoms: incapaci- tating. From these data, a number of mathematical mod- els were used to assess responses arriving at a conclusion that “An important advantage of this approach is that all relevant data can be used in the derivation as opposed to a NOAEL for the critical effect. The benefit of doing so allows health risks to be estimated across various exposure levels.” This approach was also endorsed by the US EPA Science Advisory Board, which observed that the process “…makes use of every bit of data available…The under- lying premise of the approach is that the severity of the effect, not the specific measurement or outcome incidence, is the information needed for assessing exposure-response relationships for non-cancer endpoints…” This detailed modeling process showed a clear threshold at 0.5 ppm for any symptoms of sensory irritation and an effective concentration at 1.5 ppm for moderate effects. Some reviews concerning the issue of formaldehyde- induced sensory irritation have commented that the above-described values have been derived for short peri- ods of time or for generally healthy individuals, with the implication that they are somehow inadequate for the general population. This erroneous assumption is based on an interpretation that such values are not sufficiently protective for longer-term exposures or for particularly sensitive individuals. However, formaldehyde-induced observed symptoms of sensory irritation are dependent on the concentration and not on the length of time (i.e., duration) of exposure as well as the fact that many of the controlled studies specifically included people who claimed to be sensitive to formaldehyde. In fact, as noted in ATSDR (2007a), the value of 0.3 ppm was considered specifically because it was below the level of concern for sensitive individuals. Even the Occupational Safety and Health Administration (OSHA) standard of 0.75 ppm is protective for sensory irritation for individuals exposed at this level for an 8-hour work shift and there is no con- cept “built into” this value for a “recovery” period as is often done for other chemicals. Several slightly lower acceptable exposure concen- trations for formaldehyde have been established (e.g., SCOEL, 0.2 ppm; BfR, 0.1 ppm; and WHO, 0.08 ppm) and although these are predominantly weight of evidence based, they incorporate an extra “margin of safety” to the derived value based on considerations other than just the concentrations eliciting the symptoms of sen- sory irritation. For example, the SCOEL value is based on several studies of acknowledged questionable design or reliability (i.e., lack of sham controls or inadequate study documentation). The BfR value of 0.1ppm is not derived solely based on sensory irritation, but rather incorporates considerations of cytotoxicity, cell proliferation, and the biologically based dose-response model for nasal tumors (none of which are relevant to sensory irritation), even while acknowledging that the epidemiological findings for nasal cancer were not causal. The value established by WHO (0.08 ppm) was based on an experimental study by Lang et al. (2008), which reported conjunctival redness and increased eye blink frequency following a 4-hour exposure of 0.5 ppm (0.63 mg/m3), which was consid- ered as the no observed adverse effect level (NOAEL). This value was adjusted by an “assessment factor” of 5, which was derived from the standard deviation of nasal pungency (i.e., sensory irritation) thresholds, leading to a value of 0.12 mg/m3 (0.09 ppm), which was rounded down to 0.1 mg/m3 or 0.08 ppm. This value was also reached based on the concept that there is no indication of accumulation of effects over time following prolonged exposure and that neither increased sensitivity nor sensi- tization was considered plausible at such concentrations in either adults or children Finally, OEHHA (Office of Environmental Health Hazard Assessment; Cal/EPA) and the INDEX project have derived even lower Chronic Reference Exposure Levels (CRELs), with formaldehyde inhalation exposure values of 0.002 ppm (2 ppb) and 1 μg/m3 (0.815 ppb), respectively. These values were derived by the applica- tion of various safety/uncertainty factors to empirically derived data. However, given that each falls close to or Critical Reviews in Toxicology