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Summary of the toxicity assessment of toluene diisocyanate conducted by the Secretary's Scientific Advisory Board on Toxic Air Pollutants
Abstract The Secretary's Scientific Advisory Board on Toxic Air Pollutants (SAB) evaluated the toxicity of toluene diisocyanate (TDI) during the course of consideration of the diisocyanate compounds. In 1986 the North Carolina Academy of Sciences issued a recommendation for 2,4-TDI based on the American Conference of Governmental Industrial Hygienists Threshold Limit Value (TLV-TWA) proposed in 1979. Since new toxicological and carcinogenic information had become available, DEHNR asked the SAB to determine the need for an updated health-based exposure recommendation for TDI. The SAB considered scientific studies related to the carcinogenicity and toxicity of TDI, listened to numerous industry presentations on the chemical and toxicological features of this compound and debated for over a year on the subject. Their final recommendation was based on the adverse respiratory effects of TDI, identified through decreases in annual forced expiratory volume in one second (FEV₁) in workers exposed chronically to commercial grade TDI (80% 2,4- and 20% 2,6-TDI isomeric mixture). Measurable decreases in FEV₁ can signal the development of an obstructive lung condition. The SAB began from a published no-adverse-effect level (NOAEL) of 0.9 ppb in exposed workers, and applied uncertainty factors to 1) account for non-continuous workplace exposures in the study and 2) protect especially sensitive subpopulations. The final SAB recommendation for TDI, which they acknowledged to be conservative for the protection of human health, is 0.03 ppb. Industry representatives involved in the deliberations advocate maintaining the current 0.07 ppb guideline for TDI. Their opinion is based on an interpretation of the literature database that supports the current 8-hour workplace standard (5 ppb) as a NOAEL. Since the SAB's final recommendation was based on a study that involved exposures to a mixture of 2,4- and 2,6-TDI isomers, it is intended to apply to total TDI, 2,4- and 2,6-TDI isomers. Data Assessment A number of biological effects have been noted following TDI exposure. TDI will cause a variety of specific and non-specific respiratory effects in humans, it is a carcinogen in laboratory animals and it can give rise to non-specific irritation of mucous membranes, skin and eyes⁽¹⁾. The SAB considered the spectrum of effects from exposure to TDI and concluded that chronic respiratory impairment, identified by testing lung function, was the most sensitive effect. Thus, drafting a recommendation intended to prevent adverse chronic respiratory effects would also be protective for all other known adverse effects resulting from TDI exposure including cancer, respiratory sensitization and irritation. Irritation: TDI is an irritant that can cause inflammation of the skin and burning of the eyes⁽²⁾. In one study involving controlled 2-year TDI inhalation exposures, rats showed signs of chronic nasal passage irritation at 50 ppb⁽³⁾. During the course of deliberations on the irritancy of TDI in humans, it was stated by one industry representative that worker studies involving both acute and chronic exposures did not show irritation below concentrations of 20 ppb (0.13 mg/m³). This value was said to be verified by both epidemiological and clinical challenge studies⁽⁴⁾. Carcinogenicity: TDI was carcinogenic at multiple sites in rats when administered in corn oil by oral administration⁽⁵⁾. However, TDI was not carcinogenic when administered to rats by the inhalation route⁽³⁾. TDI can be metabolized in the body to toluene diamine (TDA). TDA is a mutagenic and carcinogenic derivative of TDI and might be the ultimate carcinogenic metabolite following TDI intake. Some researchers have speculated that the positive carcinogenic response seen following oral administration of TDI is due to hydrolysis of TDI to TDA in the acid environment of the gut. Although the inhalation study produced negative results, there were enough questions about the way the study was conducted that the Board decided the results were not conclusive. Risk assessment calculations were made utilizing the positive carcinogenesis data from the aforementioned National Toxicology Program (NTP) study involving oral administration of commercial grade TDI. Little is known about the mode of action for TDI carcinogensis. In the absence of mechanistic information, it is standard risk assessment practice to assume a linear response at all dose levels. That is, the rate of positive response seen at the experimental doses can be linearly extrapolated back to zero, and from this line the dose responsible for a given increase in cancer incidence can be determined. Since TDI is designated as a probable human carcinogen, the dose level which represents 10^-5 excess risk (i.e. 1 excess case of cancer per 100,000 individuals) was determined in this fashion. This value was then converted to inhalation dose for humans, using important assumptions such as a body weight scaling factor and 100% absorption by the inhalation route. The resulting value, designed to be conservative for protection against the development of cancer, was calculated as 0.45 ppb (0.003 mg/m³). Respiratory Effects: The primary route of human exposure to TDI is by inhalation of the vapor. Inhalation of the reactive isocyanates can result in a variety of adverse respiratory effects at low levels of exposure. Exposure to TDI has been linked with the development of asthma in polyurethane foam workers ("isocyanate asthma"). This type of reaction can involve bronchial hyperresponsiveness, chest tightness and/or labored breathing⁽⁷⁾. Individuals who have become sensitized to TDI through previous exposures may develop asthma-like symptoms at exposure levels which do not produce these effects in non-sensitized individuals. The TDI-specific response may decrease after several months without TDI exposure, but an increased sensitivity to other asthma-inducing agents can remain strong for over a year even in the absence of exposure to TDI⁽⁸⁾. Exposure to TDI has also been linked to other respiratory effects. Long-term TDI exposure has been shown to produce chronic airway disorders including chronic bronchitis and allergic alveolitis⁽⁶⁾. In addition, there is evidence that low level long-term exposures of non-sensitized individuals to TDI can result in gradually declining lung function, which may signal the development of a chronic obstructive lung condition⁽⁹⁾. The SAB considered the spectrum of respiratory endpoints during their risk assessment of TDI. They specifically focused attention on the development of pulmonary effects in occupationally exposed workers. Board members reviewed a number of worker studies involving exposure to low airborne levels of TDI and heard presentations made by industry experts on the development of pulmonary effects in exposed workers^(2,4,9). The SAB concluded that the Diem, et al, study involving occupational exposures to airborne TDI was the most appropriate study for air toxics risk assessment purposes⁽⁹⁾. This study involved 277 workers beginning work in a new TDI manufacturing plant. These workers were followed for up to 5 years with periodic measurements taken to estimate TDI exposure and breathing performance. After controlling for smoking, a correlation between exposure to TDI and annual decreases in forced expiratory volume in one second (FEV₁) was noted in the high-exposure group. This type of decrease in lung function is a chronic effect that was detected in never-smokers following continuous low-level workplace exposure to TDI. The average exposure level at which no effect was seen (NOAEL) was determined to be 0.9 ppb for this study^(9,10). The SAB used two uncertainty factors in arriving at their final TDI recommendation. Using the NOAEL from the Diem study, the SAB agreed that an adjustment should be made to compensate for the non-continuous, workday exposures seen in the study since the intermittent "8 hours-on / 16 hours-off" exposure pattern may underestimate effects from continuous exposure to TDI. Applying a mathematical formula to relate the workplace NOAEL to a continuous exposure situation resulted in an adjusted NOAEL of 0.3 ppb. The SAB then applied an uncertainty factor of 10 to protect especially sensitive individuals in the population. Worker studies typically involve healthy young men, and relying solely on human data from these studies can underestimate the effect on potentially sensitive subpopulations such as children, women, the elderly or those with pre-existing respiratory ailments. In addition, there is a considerable amount of information indicating a wide inter-individual variability in response to TDI. Incorporating an uncertainty factor of 10 for the protection of sensitive subpopulations is standard practice for this Board and many other risk assessment bodies. The final SAB recommendation, based on the results seen in the Diem study, is 0.03 ppb (0.0002 mg/m³). Conclusion Annual decreases in FEV₁ can signal the development of chronic airway obstruction. This is a respiratory effect that can be measured in the laboratory by objective means. TDI was shown to produce annual decreases in FEV₁ in exposed workers. The decreased FEV₁ measurements detected in the Diem study were real and statistically significant between low and high exposure groups. Using the Diem data, the SAB established a NOAEL of 0.9 ppb as a starting point, adjusted that value to account for the non-continuous exposures occuring in the study, and applied a final uncertainty factor of 10 to account for variability in individual susceptibility. Their final recommendation was deemed to be health protective against all known adverse health effects arising from exposure to TDI, including respiratory, carcinogenic and irritant effects. The SAB has expressed an intermediate level of confidence in the current risk assessment. At the 55th SAB meeting, the SAB acknowledged that their final TDI value was a conservative estimate, based on exposure measurements averaged out over work shifts. However, the SAB considered the Diem study of high quality and appropriate for human health risk assessment purposes. The decision to accept 0.03 ppb as the recommended level for total TDI isomers was a unanimous one and was reconfirmed as recently as May 8, 1997. Industry representatives disagree with the SAB's interpretation of 0.9 ppb TDI as a valid NOAEL⁽¹¹⁾. They feel that the 1.1 ppb cumulative exposure lowest adverse effect level (LOAEL) estimate identified in the Diem study is more representative of effects generated by short-term high-level exposures⁽¹¹⁾. In the Diem paper, it is stated that "the different health effects observed in these groups supports the NIOSH-recommended standard of 5 ppb [0.036 mg/m³] TDI as an 8-h TWA." Dr. Tim Landry of Dow Chemical, a representative of the Chemical Manufacturers Association (CMA), has advocated maintaining the current AAL of 0.07 ppb for TDI. The CMA feels that the current 8-hour workplace standard of 5 ppb TDI is protective of worker health, and the current North Carolina AAL of 0.07 ppb TDI is adequately protective of public health. On April 8, 1997, the SAB was asked to restate whether their recommendation should be interpreted as applying to one (2,4-) or both (2,4- and 2,6-) isomers of TDI. After considering published evidence that both isomers of TDI could cause similar respiratory symptoms⁽¹²⁾, all SAB members indicated that their recommendation should apply to total TDI, 2,4- and 2,6-isomers. Averaging Time The Division of Air Quality recommends that a 24 hour averaging time be applied to the adopted AAL guideline for TDI. This recommendation is consistent with the guidelines prescribed by the North Carolina Academy of Sciences which includes 24-hour averaging periods for chronic toxicants. Calculations NOAEL = 0.9 ppb (based on 8 hour workplace exposures, Diem, et al, 1982) Adjustment for continuous exposure 0.9 ppb * (10 m³ air breathed/workday) / (20 m³ air breathed/day) * 5 day workweek / 7 day workweek = 0.3 ppb Adjustment for susceptible subpopulations 0.3 ppb / 10 = 0.03 ppb Final SAB Recommendation = 0.03 ppb (0.0002 mg/m³), 24-hour averaging period References IRIS, (1995). "2,4-/2,6-Toluene diisocyanate mixture." Integrated Risk Information System, U.S. Environmental Protection Agency. ACGIH (1993). Documentation of the Threshold Limit Values and Biological Indices. Toluene-2,4-diisocyanate. Fifth Edition, 1581-1589. Loeser E, (1983). "Long-term toxicity and carcinogenicity studies with 2,4/2,6-toluene-diisocyanate (80/20) in rats and mice." Toxicology Letters, 15, 71-81. Garabrant D, (1995). Presentation before the North Carolina Secretary's Scientific Advisory Board (SAB) on Toxic Air Pollutants, SAB Meeting #40, June 19, 1995. National Toxicology Program (NTP), (1986). "Toxicology and carcinogenesis studies of commercial grade 2,4- (80%) and 2,6- (20%) toluene diisocyanate." NTP Technical Report 251, National Institute Health Sciences, Bethesda, MD. Baur X, Marek W, Ammon J, et al. (1994). "Respiratory and other hazards of isocyanates." Int. Arch. Occup. Environ. Health. 66, 141-152. Moscato G, Dellabianca A, Vinci G, Candura SM and Bossi MC, (1991). "Toluene diisocyanate-induced asthma: Clinical findings and bronchial responsiveness in 113 exposed subjects with work-related respiratory symptoms." J. Occup. Med. 33(6), 720-725. Paggiaro PL, Vagaggini B, Dente FL, Bacci E, et al. (1993) "Bronchial hyperresponsiveness and toluene diisocyanate. Long-term change in sensitized asthmatic subjects." Chest, 103(4), 1123-1128. Diem JE, Jones RN, Hendrick DJ, et al. (1982). "Five-year longitudinal study of workers employed in a new toluene diisocyanate manufacturing plant." Am. Rev. Resp. Dis., 126, 420-428. Hasselblad V, (1993). Analysis of studies of workers exposed to toluene diisocyanate. Report prepared for U.S. EPA, Environmental Criteria and Assessment Office, Research Triangle Park, NC. Correspondence between Beth Mileson, PhD, Toxicologist for the North Carolina Department of the Environment, Health and Natural Resources and Mary K. Donohue, Associate Toxicologist with Olin Corporation, February 22, 1996. Banks DE, et al. (1989). Role of inhalation challenge testing in the diagnosis of isocyanate-induced asthma, 95(2), 414-423.

Summary of the toxicity assessment of toluene diisocyanate conducted by the Secretary's Scientific Advisory Board on Toxic Air Pollutants

Abstract
The Secretary's Scientific Advisory Board on Toxic Air Pollutants (SAB) evaluated the toxicity of toluene diisocyanate (TDI) during the course of consideration of the diisocyanate compounds. In 1986 the North Carolina Academy of Sciences issued a recommendation for 2,4-TDI based on the American Conference of Governmental Industrial Hygienists Threshold Limit Value (TLV-TWA) proposed in 1979. Since new toxicological and carcinogenic information had become available, DEHNR asked the SAB to determine the need for an updated health-based exposure recommendation for TDI. The SAB considered scientific studies related to the carcinogenicity and toxicity of TDI, listened to numerous industry presentations on the chemical and toxicological features of this compound and debated for over a year on the subject. Their final recommendation was based on the adverse respiratory effects of TDI, identified through decreases in annual forced expiratory volume in one second (FEV₁) in workers exposed chronically to commercial grade TDI (80% 2,4- and 20% 2,6-TDI isomeric mixture). Measurable decreases in FEV₁ can signal the development of an obstructive lung condition. The SAB began from a published no-adverse-effect level (NOAEL) of 0.9 ppb in exposed workers, and applied uncertainty factors to 1) account for non-continuous workplace exposures in the study and 2) protect especially sensitive subpopulations. The final SAB recommendation for TDI, which they acknowledged to be conservative for the protection of human health, is 0.03 ppb. Industry representatives involved in the deliberations advocate maintaining the current 0.07 ppb guideline for TDI. Their opinion is based on an interpretation of the literature database that supports the current 8-hour workplace standard (5 ppb) as a NOAEL. Since the SAB's final recommendation was based on a study that involved exposures to a mixture of 2,4- and 2,6-TDI isomers, it is intended to apply to total TDI, 2,4- and 2,6-TDI isomers.

Data Assessment
A number of biological effects have been noted following TDI exposure. TDI will cause a variety of specific and non-specific respiratory effects in humans, it is a carcinogen in laboratory animals and it can give rise to non-specific irritation of mucous membranes, skin and eyes⁽¹⁾. The SAB considered the spectrum of effects from exposure to TDI and concluded that chronic respiratory impairment, identified by testing lung function, was the most sensitive effect. Thus, drafting a recommendation intended to prevent adverse chronic respiratory effects would also be protective for all other known adverse effects resulting from TDI exposure including cancer, respiratory sensitization and irritation.

Irritation: TDI is an irritant that can cause inflammation of the skin and burning of the eyes⁽²⁾. In one study involving controlled 2-year TDI inhalation exposures, rats showed signs of chronic nasal passage irritation at 50 ppb⁽³⁾. During the course of deliberations on the irritancy of TDI in humans, it was stated by one industry representative that worker studies involving both acute and chronic exposures did not show irritation below concentrations of 20 ppb (0.13 mg/m³). This value was said to be verified by both epidemiological and clinical challenge studies⁽⁴⁾.
Carcinogenicity: TDI was carcinogenic at multiple sites in rats when administered in corn oil by oral administration⁽⁵⁾. However, TDI was not carcinogenic when administered to rats by the inhalation route⁽³⁾. TDI can be metabolized in the body to toluene diamine (TDA). TDA is a mutagenic and carcinogenic derivative of TDI and might be the ultimate carcinogenic metabolite following TDI intake. Some researchers have speculated that the positive carcinogenic response seen following oral administration of TDI is due to hydrolysis of TDI to TDA in the acid environment of the gut. Although the inhalation study produced negative results, there were enough questions about the way the study was conducted that the Board decided the results were not conclusive.

Risk assessment calculations were made utilizing the positive carcinogenesis data from the aforementioned National Toxicology Program (NTP) study involving oral administration of commercial grade TDI. Little is known about the mode of action for TDI carcinogensis. In the absence of mechanistic information, it is standard risk assessment practice to assume a linear response at all dose levels. That is, the rate of positive response seen at the experimental doses can be linearly extrapolated back to zero, and from this line the dose responsible for a given increase in cancer incidence can be determined. Since TDI is designated as a probable human carcinogen, the dose level which represents 10^-5 excess risk (i.e. 1 excess case of cancer per 100,000 individuals) was determined in this fashion. This value was then converted to inhalation dose for humans, using important assumptions such as a body weight scaling factor and 100% absorption by the inhalation route. The resulting value, designed to be conservative for protection against the development of cancer, was calculated as 0.45 ppb (0.003 mg/m³).
Respiratory Effects: The primary route of human exposure to TDI is by inhalation of the vapor. Inhalation of the reactive isocyanates can result in a variety of adverse respiratory effects at low levels of exposure. Exposure to TDI has been linked with the development of asthma in polyurethane foam workers ("isocyanate asthma"). This type of reaction can involve bronchial hyperresponsiveness, chest tightness and/or labored breathing⁽⁷⁾. Individuals who have become sensitized to TDI through previous exposures may develop asthma-like symptoms at exposure levels which do not produce these effects in non-sensitized individuals. The TDI-specific response may decrease after several months without TDI exposure, but an increased sensitivity to other asthma-inducing agents can remain strong for over a year even in the absence of exposure to TDI⁽⁸⁾.

Exposure to TDI has also been linked to other respiratory effects. Long-term TDI exposure has been shown to produce chronic airway disorders including chronic bronchitis and allergic alveolitis⁽⁶⁾. In addition, there is evidence that low level long-term exposures of non-sensitized individuals to TDI can result in gradually declining lung function, which may signal the development of a chronic obstructive lung condition⁽⁹⁾.

The SAB considered the spectrum of respiratory endpoints during their risk assessment of TDI. They specifically focused attention on the development of pulmonary effects in occupationally exposed workers. Board members reviewed a number of worker studies involving exposure to low airborne levels of TDI and heard presentations made by industry experts on the development of pulmonary effects in exposed workers^(2,4,9). The SAB concluded that the Diem, et al, study involving occupational exposures to airborne TDI was the most appropriate study for air toxics risk assessment purposes⁽⁹⁾. This study involved 277 workers beginning work in a new TDI manufacturing plant. These workers were followed for up to 5 years with periodic measurements taken to estimate TDI exposure and breathing performance. After controlling for smoking, a correlation between exposure to TDI and annual decreases in forced expiratory volume in one second (FEV₁) was noted in the high-exposure group. This type of decrease in lung function is a chronic effect that was detected in never-smokers following continuous low-level workplace exposure to TDI. The average exposure level at which no effect was seen (NOAEL) was determined to be 0.9 ppb for this study^(9,10).

The SAB used two uncertainty factors in arriving at their final TDI recommendation. Using the NOAEL from the Diem study, the SAB agreed that an adjustment should be made to compensate for the non-continuous, workday exposures seen in the study since the intermittent "8 hours-on / 16 hours-off" exposure pattern may underestimate effects from continuous exposure to TDI. Applying a mathematical formula to relate the workplace NOAEL to a continuous exposure situation resulted in an adjusted NOAEL of 0.3 ppb. The SAB then applied an uncertainty factor of 10 to protect especially sensitive individuals in the population. Worker studies typically involve healthy young men, and relying solely on human data from these studies can underestimate the effect on potentially sensitive subpopulations such as children, women, the elderly or those with pre-existing respiratory ailments. In addition, there is a considerable amount of information indicating a wide inter-individual variability in response to TDI. Incorporating an uncertainty factor of 10 for the protection of sensitive subpopulations is standard practice for this Board and many other risk assessment bodies. The final SAB recommendation, based on the results seen in the Diem study, is 0.03 ppb (0.0002 mg/m³).

Conclusion
Annual decreases in FEV₁ can signal the development of chronic airway obstruction. This is a respiratory effect that can be measured in the laboratory by objective means. TDI was shown to produce annual decreases in FEV₁ in exposed workers. The decreased FEV₁ measurements detected in the Diem study were real and statistically significant between low and high exposure groups. Using the Diem data, the SAB established a NOAEL of 0.9 ppb as a starting point, adjusted that value to account for the non-continuous exposures occuring in the study, and applied a final uncertainty factor of 10 to account for variability in individual susceptibility. Their final recommendation was deemed to be health protective against all known adverse health effects arising from exposure to TDI, including respiratory, carcinogenic and irritant effects.

The SAB has expressed an intermediate level of confidence in the current risk assessment. At the 55th SAB meeting, the SAB acknowledged that their final TDI value was a conservative estimate, based on exposure measurements averaged out over work shifts. However, the SAB considered the Diem study of high quality and appropriate for human health risk assessment purposes. The decision to accept 0.03 ppb as the recommended level for total TDI isomers was a unanimous one and was reconfirmed as recently as May 8, 1997.

Industry representatives disagree with the SAB's interpretation of 0.9 ppb TDI as a valid NOAEL⁽¹¹⁾. They feel that the 1.1 ppb cumulative exposure lowest adverse effect level (LOAEL) estimate identified in the Diem study is more representative of effects generated by short-term high-level exposures⁽¹¹⁾. In the Diem paper, it is stated that "the different health effects observed in these groups supports the NIOSH-recommended standard of 5 ppb [0.036 mg/m³] TDI as an 8-h TWA." Dr. Tim Landry of Dow Chemical, a representative of the Chemical Manufacturers Association (CMA), has advocated maintaining the current AAL of 0.07 ppb for TDI. The CMA feels that the current 8-hour workplace standard of 5 ppb TDI is protective of worker health, and the current North Carolina AAL of 0.07 ppb TDI is adequately protective of public health.

On April 8, 1997, the SAB was asked to restate whether their recommendation should be interpreted as applying to one (2,4-) or both (2,4- and 2,6-) isomers of TDI. After considering published evidence that both isomers of TDI could cause similar respiratory symptoms⁽¹²⁾, all SAB members indicated that their recommendation should apply to total TDI, 2,4- and 2,6-isomers.

Averaging Time
The Division of Air Quality recommends that a 24 hour averaging time be applied to the adopted AAL guideline for TDI. This recommendation is consistent with the guidelines prescribed by the North Carolina Academy of Sciences which includes 24-hour averaging periods for chronic toxicants.

Calculations

NOAEL = 0.9 ppb (based on 8 hour workplace exposures, Diem, et al, 1982)

Adjustment for continuous exposure

0.9 ppb

* (10 m³ air breathed/workday) / (20 m³ air breathed/day)

* 5 day workweek / 7 day workweek

= 0.3 ppb

Adjustment for susceptible subpopulations

0.3 ppb / 10 = 0.03 ppb

Final SAB Recommendation = 0.03 ppb (0.0002 mg/m³), 24-hour averaging period

References

IRIS, (1995). "2,4-/2,6-Toluene diisocyanate mixture." Integrated Risk Information System, U.S. Environmental Protection Agency.
ACGIH (1993). Documentation of the Threshold Limit Values and Biological Indices. Toluene-2,4-diisocyanate. Fifth Edition, 1581-1589.
Loeser E, (1983). "Long-term toxicity and carcinogenicity studies with 2,4/2,6-toluene-diisocyanate (80/20) in rats and mice." Toxicology Letters, 15, 71-81.
Garabrant D, (1995). Presentation before the North Carolina Secretary's Scientific Advisory Board (SAB) on Toxic Air Pollutants, SAB Meeting #40, June 19, 1995.
National Toxicology Program (NTP), (1986). "Toxicology and carcinogenesis studies of commercial grade 2,4- (80%) and 2,6- (20%) toluene diisocyanate." NTP Technical Report 251, National Institute Health Sciences, Bethesda, MD.
Baur X, Marek W, Ammon J, et al. (1994). "Respiratory and other hazards of isocyanates." Int. Arch. Occup. Environ. Health. 66, 141-152.
Moscato G, Dellabianca A, Vinci G, Candura SM and Bossi MC, (1991). "Toluene diisocyanate-induced asthma: Clinical findings and bronchial responsiveness in 113 exposed subjects with work-related respiratory symptoms." J. Occup. Med. 33(6), 720-725.
Paggiaro PL, Vagaggini B, Dente FL, Bacci E, et al. (1993) "Bronchial hyperresponsiveness and toluene diisocyanate. Long-term change in sensitized asthmatic subjects." Chest, 103(4), 1123-1128.
Diem JE, Jones RN, Hendrick DJ, et al. (1982). "Five-year longitudinal study of workers employed in a new toluene diisocyanate manufacturing plant." Am. Rev. Resp. Dis., 126, 420-428.
Hasselblad V, (1993). Analysis of studies of workers exposed to toluene diisocyanate. Report prepared for U.S. EPA, Environmental Criteria and Assessment Office, Research Triangle Park, NC.
Correspondence between Beth Mileson, PhD, Toxicologist for the North Carolina Department of the Environment, Health and Natural Resources and Mary K. Donohue, Associate Toxicologist with Olin Corporation, February 22, 1996.
Banks DE, et al. (1989). Role of inhalation challenge testing in the diagnosis of isocyanate-induced asthma, 95(2), 414-423.