Benzidine exposure

Toxicology. Benzidine exposure is associated with a high incidence of bladder cancer in humans. 

In a 30-year follow-up of a cohort of 984 workers employed at a benzidine manufacturing facility there was a significant excess of bladder tumors among men with the highest estimated level of benzidine exposure. The bladder cancer risk declined in those first employed after 1950, when preventive measures were instituted. 

Benzidine exposure has been associated with chromosomal aberrations and polyploidy in the circulating peripheral lymphocytes of workers, micronucleus induction in rodents,... 

Zavon MR, Hoegg U, Bingham E Benzidine exposure as a cause of bladder tumors. Arch Environ Health 27 1-7, 1973... 

In addition the role played by the sorbent on which the chromatography is carried out must not be neglected. For instance, it is only on aliuninium oxide layers and not on silica gel that it is possible to detect caffeine and codeine by exposure to chlorine gas and treatment with potassium iodide — benzidine [37]. The detection limits can also depend on the sorbent used. The detection limit is also a fimction of the h/ f value. The concentration of substance per chromatogram zone is greater when the migration distance is short than it is for components with high h/ f values. Hence, compounds with low h/ f values are more sensitively detected. 

Historically, bladder tumors have been associated with exposures in the aniline dye industry. However, conclusive evidence for any one particular exposure could not be obtained in these studies since the workers were exposed to many chemicals within the same work area. For example, Case et al. (1954) investigated the incidence of bladder tumors among British workers in the chemical dye industry. In addition to aniline, the workers were exposed to other aromatic amines, including a- and P-naphthylamine, benzidine, and auramine. Although exposures could not be quantified, there was insufficient evidence to suggest that aniline was a cause of bladder cancers. More recent studies indicate that P-naphthylamine, 4-aminodiphenyl, 4-nitrodiphenyl, 4,4-diaminodiphenyl, or o-toluidine may be involved in increased cancers in the dye industry (Ward et al. 1991 Benya and Cornish 1994). 

The available database limits analysis of exposures in two ways. First, very little information is available concerning the manufacturing processes used in the production of phenylbutazone and sulfinpyrazone, the two drugs that use 1,2-diphenylhydrazine as a starting material. A better understanding of these processes would allow the estimation of worker exposure potentials. Second, dye manufacturers in the United States no longer produce benzidine based dyes (the last manufacturer stopped production in 1988) and the number of workers potentially exposed to... 

Marhold J. 1951. [A case of tumour of the bladder following exposure to benzidine.] Pracovni Lekarstvi 3 272-274. (Czech)... 

Levels of exposure associated with carcinogenic effects (Cancer Effect Levels, CELs) of 3,3 -dichloro-benzidine are indicated in Table 2-1 and Figure 2-1. Because cancer effects could occur at lower exposure levels, Figure 2-1 also shows a range for the upper bound of estimated excess risks, ranging from a risk of 1 in 10,000 to 1 in 10,000,000 (10 to 10 ), as developed by EPA. 

In one of these reports, no bladder tumors were foimd in a group of 35 workers who handled only 3,3 -dichlorobenzidine in the same dyestuff plant, bladder tumors occurred in 3 out of 14 workers exposed to both benzidine and 3,3 -dichlorobenzidine. The investigator reported a total exposure time of 68,505 hours, equivalent to nearly 140 full-time working years (Gadian 1975). 

No cases of bladder tumors were found in an epidemiology study of 259 workers exposed to dry and semi-dry 3,3 -dichlorobenzidine base and hydrochloride. Cytological analyses of the urine (Papanicolaou tests) were negative. Workers were exposed to an average of less than 16 years each to 3,3 -dichloro-benzidine, which means that an adequate exposure dmation and/or the latent period following exposm-e may not have been reached for tumor expression (MacIntyre 1975). 

No studies were located regarding cancer efFeets in animals after inhalation exposure to 3,3 -diehloro-benzidine. However, cancer effects have been observed in animal studies where 3,3 -dichlorobenzidine was administered orally or by other routes. See Seetions 2.2.2.8 and 2.5 for further information. 

No studies were located regarding neurological effects in humans after oral exposure to 3,3 -dichloro-benzidine. 

No studies were located regarding lethal effects in humans after dermal exposure to 3,3 -dichloro-benzidine. The minimum dermal lethal dose for 3,3 -dichlorobenzidine (free base) for male and female New Zealand albino rabbits with skin intact was reported to be greater than 8,000 mg/kg (Gerarde and Gerarde 1974). The cause of death was not discussed. No discernible skin irritation was observed when 3,3 -dichlorobenzidine dihydrochloride was applied to the intact or abraded skin of rabbits the dose was not provided (Gerarde and Gerarde 1974). This minimum dermal lethal dose in female New Zealand albino rabbits is shown in Table 2-2. Dermal exposure is not likely to cause death in humans. 

Death. No deaths were reported in humans from inhalation, oral, or dermal exposure to 3,3 -diehloro-benzidine. In animals, 3,3 -dichlorobenzidine eaused no deaths in rats exposed by the inhalation route in eoneentrations as high as 23,700 mg/m for 2 hours per day for 7 days (Gerarde and Gerarde 1974). In addition, the estimated aeute oral LDjg for rats (7,070 mg/kg for the free base and 3,820 mg/kg for the dihydroehloride salt) and the minimum dermal lethal dose for male and female New Zealand albino rabbits (>8,000 mg/kg) for 3,3 -diehlorobenzidine suggested that the lethal toxieity of 3,3 -dichlorobenzidine is minimal (Gerarde and Gerarde 1974). Consequently, it is unlikely that death will oeeur in humans exposed to 3,3 -diehlorobenzidine at the levels at whieh it oeeurs at hazardous waste sites. 

Systemic Effects. Dermatitis appears to be the only effect of 3,3 -dichlorobenzidine (free base) exposure for which evidence exists in humans (Gerarde and Gerarde 1974). Gastrointestinal upset and upper respiratory tract infections have also been reported by workers, but the role of 3,3 -dichloro-benzidine was imcertain. 3,3 -Dichlorobenzidine has not been found to cause these effects in experimental animals. 

Gastrointestinal Effects. Gastrointestinal upset was one of the symptoms reported by employees who worked with 3,3 -diehlorobenzidine dihydroehloride (dihydro salt of 3,3 -diehlorobenzidine) (Gerarde and Gerarde 1974). However, there is no eonelusive evidence that 3,3 -dichlorobenzidine eaused these gastrointestinal upsets since there was exposure to other chemieals as well. In addition, 3,3 -diehloro-benzidine has not been found to eause any of these effects in experimental animals. Therefore, it is unlikely that exposure to 3,3 -diehlorobenzidine at hazardous waste sites will cause gastrointestinal effeets in humans. 

Hepatic Effects. No studies were located regarding hepatic effects in humans after exposure to 3,3 -dichlorobenzidine. Information from animal studies on the liver effects of exposure to 3,3 -dichloro-benzidine suggests that exposme to sufficiently high levels of the compoimd could cause liver injury as indicated by modest elevation in serum transaminase activity, fatty liver (Stula et al. 1978), decrease in hepatic vitamin E, and lipid peroxidation (Iba 1987a Iba and Lang 1988 Iba and Thomas 1988). Some of these effects may contribute to the liver tumors induced. However, it is not known whether these liver injuries will occur in humans exposed to 3,3 -dichlorobenzidine at levels at which it occurs at hazardous... 

Ocular Effects. No studies were located regarding ocular effects in humans after exposure to 3,3 -dichlorobenzidine by any route. No adverse effects on the eye were noted when dichlorobenzidine (isomer unspecified, free base) was directly placed in the conjunctival sac of the eye of rabbits (Gerarde and Gerarde 1974). However, 0.1 mL 3,3 -dichlorobenzidine dihydrochloride (dihydro salt of 3,3 -dichloro-benzidine) in a 20% com oil suspension produced erythema, pus, and comeal opacity, giving a 76% score in the Draize test within an hour when placed in the conjunctival sac of the eye of the rabbit (Gerarde and Gerarde 1974). Apparently, the irritant effects of hydrochloric acid Ifom the salt-compoimd contributed... 

Immunological and Lymphoreticular Effects. No studies were loeated regarding immunological and/or lymphoreticular effects in humans or animals following exposure to 3,3 -diehlorobenzidine by any route of exposure. The immime system does not appear to be a sensitive target of 3,3 -dichlorobenzidine toxicity. Consequently, immune system disruptions are not expected in humans exposed to 3,3 -dichloro-benzidine at the levels at which it occurs at hazard waste sites. 

A susceptible population is defined as one which will exhibit a different or enhanced response to a chemical compared to most persons exposed to the same level of exposure. Reasons may include genetic makeup, age, health and nutritional status, and exposure to other toxic substances (e g., cigarette smoke). For this chemical, these parameters may result in reduced detoxification or excretion of 3,3 -dichloro-benzidine, or compromised function of target organs affected by 3,3 -dichlorobenzidine. Populations who are at greater risk due to their unusually high exposure to 3,3 -dichlorobenzidine are discussed in Section 5.6, Populations With Potentially High Exposure. 

Developmental Toxicity. No studies were found regarding developmental toxicity of 3,3 -dichloro-benzidine in humans. Animal studies have shown that 3,3 -dichlorobenzidine and/or metabolites may be transferred across the placenta and or through maternal milk to the offspring and may affect the growth of the kidneys after parenteral exposure during pregnancy (Golub 1972 Shabad et al. 1972) or induce... 

No studies were located that monitored human tissues for content of 3,3 -dichlorobenzidine or its metabolites. 3,3 -Dichlorobenzidine is excreted in urine. If 3,3 -dichlorobenzidine and metabolites can be detected and correlated with exposure, it may be possible to correlate urinary levels of 3,3 -dichloro-benzidine or its metabolites, with systemic effects. 

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