Carbon tetrachloride

Epidemiological data

Administrative data

Endpoint:

epidemiological data

Type of information:

experimental study

Adequacy of study:

key study

Reliability:

2 (reliable with restrictions)

Data source

Reference

Reference Type:

publication

Title:

Hepatic function in workers occupationally exposed to carbon tetrachloride.

Author:

Tomenson JA, Baron CE, O'Sullivan JJ, Edwards JC, Stonard MD, Walker RJ, Fearnley DM.

Year:

1995

Bibliographic source:

Occup Environ Med, vol. 52, no. 8, p. 508-14.

Materials and methods

Study type:

cross sectional study

Endpoint addressed:

repeated dose toxicity: inhalation

Test guideline

Qualifier:

no guideline followed

Principles of method if other than guideline:

cross sectional study on 135 exposed and 276 non exposed workers. Exposed workers were situated at three different sites, non exposed workers were from one of these sites and from an additional site. groups were well matched for demographic details and alcohol consumption. The exposed workers were subdevided into 3 exposure groups (low, medium high) based on a combination of personal exposure measurement data and by judgement of a professional industrial hygienist.

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Carbon tetrachloride

EC Number:

200-262-8

EC Name:

Carbon tetrachloride

Cas Number:

56-23-5

Molecular formula:

CCl4

IUPAC Name:

tetrachloromethane

Details on test material:

- Name of test material (as cited in study report): carbon terachloride
- exposure during production of procedure and maintanace of the production plant

Method

Type of population:

occupational

Ethical approval:

confirmed and informed consent free of coercion received

Exposure assessment:

estimated

Details on exposure:

the exposure was partly available from historical personal monitoring data (especially for the highly exposed individuals) and was partly assessed by judgement of a professional industrial hygienist (see table 3)

TYPE OF EXPOSURE:
inhalative exposure

TYPE OF EXPOSURE MEASUREMENT:
- historical personal monitoring data: unclear, very likely Area air sampling or Personal sampling


EXPOSURE LEVELS: mean result < 1 ppm (6.4 mg/m³)
mean result 1 - 3.9 ppm (6.4 - 25 mg/m³)
mean result > 3 ppm


EXPOSURE PERIOD: categories: < 1 yr, 1 - 5 yrs, > 5 yrs



POSTEXPOSURE PERIOD:
not applicable

Statistical methods:

- univariate and multivariate analysis of variance
- for certain biochemical and haematological measurements logarithmic transformation were used to have closer agreement with normally distributed errors and a linear model
- terms in the models: exposure category, age, sampling time (first or second phase) and a measure of alcohol intake based on the quantity and frequency of consumption
- the possibility of a synergistic reaction between exposure to carbon tetrachloride and alcohol consumption was examined by including an interaction term between the two factors in the linear model

Results and discussion

Results:

The finding of a significant difference between exposed and control groups in the multivariate analysis of alanine transaminase, aspartate transaminase, alkaline phosphatase, and glutamyl transferase is consistent with the excess of abnormal results in the exposed group for two of these variables, alanine transaminase and y-glutamyl transferase. The univariate analysis of variance did not show significant differences between the exposed and non-exposed workers in these four variables, but there was a suggestion of a dose response for alkaline phosphatase and yglutamyl transferase. The lack of a significant dose-response effect may be due to imprecision in the exposure ranking of each worker.
No synergistic effect betweeen CTC exposure and alcohol consumption could be detected.
Though significant differences between exposed and control groups were noted in the univariate analysis for haemoglobin, packed cell volume, and red blood count no indication of any exposure-effect relation for these variables was found.

Confounding factors:

- smoking status was not assessed

Strengths and weaknesses:

- strengths: groups nicely matched for demographic and alcohol consumation parameters
- weaknesses:
- only single measurement of biochemical and haemotological parameters
- limited accuracy of the assessment of exposure to CTC especially for the low exposure group (see table 3)
- biphasic measurement of biochemical and haemological parameters that might have had an bias

Any other information on results incl. tables

EXPOSURE - the exposure was determined as described above and the exposed workers were categorised in 3 groups - Number of measurements: 1, concerning blood and biochemical parameters unclear, concerning historical personal monitoring data FINDINGS - Matching: study and control groups were well matched for age, height, weight, work patterns and alcohol consumption (see table 1) - Univariate analyses of variance for all 21 of the biochemical and haematological variables (see table 2): - significant differences between exposed and non-exposed workers for only three variables, haemoglobin (P 0 001), packed cell volume and red blood count (P 0-0 1) which were decided to be incidentially and not mec hanistically related to the exposure - significant relations with alcohol consumption were found for total bile acids (P 0-001), yrglutamyl transferase (P 0-01), red blood count, mean corpuscular volume, and triglycerides (P 0 05). - The multivariate analysis of variance of the variables alkaline phosphatase, aspartate transaminase, alanine transaminase, and gama-glutamyl transferase: - significant difference (P 0 05) between exposed and non-exposed workers - Pairwise comparisons: - a significant increase (P 0.05) in the concentrations of alkaline phosphatase and gamma-glutamyl transferase in the medium exposure group and a comparable, but non-significant increase in the high exposure group - normal range analysis: - proportion of exposed workers above the upper limit was significantly raised for two variables, alanine transaminase (P 005) and gama- glutamyl transferase (P 0001). - a little difference between the proportions of exposed and non-exposed workers below the lower limits of the haematological variables, haemoglobin, packed cell volume, and red blood count - No effect correlated to the production site INCIDENCE / CASES - Incidence: 3 cases of one or more parameters 3 SD outside the control group - Causes for the deviations: 1 case: non exposure related liver disease 1 case: non-Hodgkin's lymphoma 1 case: haemochromatosis (member of the control group)

Table 1 Alcohol consumption of exposed and control populations 

Alcohol consumption	Control (%)	Exposed (%)
Low:	26.5	23.0
Never drink
1-2 Units no more than 1-2 times/week
3-7 Units no more than 2-3 times/month
> 8 Units no more than once/month
Medium:	26.9	21.5
1-2 Units at least 3-4 times/week
5-7 Units 3-4 times/week
> 8 Units 1-2 times / week
High:	27.3	28.9
3-4 Units at least 3-4 times/week
4-7 Units 3-4 times/week
> 8 Units 1-2 times/week
Very high:	19.6	26.7
5-7 Units every day
> 8 Uni8ts at least 3-4 times/week

Table 2 Exposure Effects - means (SEM) of selected biochemical and haematological indices for different exposure categories

	None	Low	Medium	High
	Mean ()	Mean ()	Mean ()	Mean ()
Alanine transaminase + (mU/ml)	20.54 (1.03)	20.35 (1.08)	20.82 (1.05)	19.39 (1.06)
Aspartate transaminase + (mU/ml)	16.48 (1.02)	15.25 (1.05)	15.88 (1.04)	15.62 (1.04)
Alkaline phosphatase + (mU/ml)	125.79 (1.02)	122.20 (1.05)	137.10* (1.04)	135.10 (1.04)
γ-glutamyl transferase + (mU/ml)	26.89 (1.05)	26.89 (1.11)	33.17* (1.08)	31.50 (1.08)
Total bile acids + (μmol/l)	1.06 (1.06)	1.00 (1.14)	1.25 (1.10)	1.28 (1.10)
5'-Nucleotidase (mU/ml)	5.89 (1.03)	6.54 (1.08)	6.25 (1.06)	5.75 (1.06)
Glutamate dehydrogenase + (mU/ml)	3.00 (1.05)	3.26 (1.10)	3.57* (1.07)	2.98 (1.07)
Haemoglobin (g/dl)	15.97 (0.08)	15.60 (0.09)	15.39*** (0.14)	15.71 (0.14)
Packed cell volume	48.54 (0.23)	47.32* (0.54)	47.32** (0.39)	48.05 (0.41)
Red blood count (x 10^12/l)	5.61 (0.03)	5.50 (0.08)	5.47* (0.06)	5.50 (0.06)

*P 0.05; **P 0.01; ***P 0.001; v control group

Geometric means (SEM) are presented for variables analysed after a logarithmic transformation

Table 3: Distribution of personal monitoring results for exposure to carbon tetrachloride in three plants.

		Number of subjects (number of results)
Category	Results mean	Plan 1	Plan 2	Plan 3	Total
Low	Measured range:
	1 ppm	0	0	0	0
	1 ppm	0	0	17 (52)	17
	Estimated	6	6	11	23
	Total				40
Medium	Measured range:
	1-1-1.9 ppm	4 (76)	0	0	4
	2-2.9 ppm	8 (190)	2 (26)	0	10
	3-3.9 ppm	4 (1)	1 (5)	0	5
	Estimated	8	1	26	35
	Total				54
High	Measured range:
	4-5.9 ppm	12 (588)	2 (11)	0	14
	6-7.9 ppm	12 (407)	2 (16)	0	14
	8-9.9 ppm	4 (135)	12 (56)	0	16
	10-11.9 ppm	0	15 (173)	0	15
	Estimated	2	0	0	2
	Total				61

Applicant's summary and conclusion

Executive summary:

The study (Tomenson, 1995) is a cross sectional study comparing on 135 workers exposed to CTC on daily levels of <1 up to 10 ppm and 276 non exposed workers. The groups are well matched for demographic and alcohol consumption parameters. Exposure levels were either assessed based on historical personal exposure data or on judgement by a professional industrial hygienist. For statistical analysis workers were grouped either for alcohol consumption, average exposure or exposure period.univariante and multivariante analysis of variance to analyse the effect of these factors on the biochemical and haematologic parameters.

There is the possibility that exposure to carbon tetrachloride was responsible for some of the effects seen in liver function enzymes as indicated by a multivariate analysis of variance of the variables alkaline phosphatase, aspartate transaminase, alanine transaminase, and gama-glutamyl transferase that revealead a significant difference (P < 0.05) between exposed and non-exposed workers.

Nevertheless, despite reservations about the accuracy of the assessment of exposure to carbon tetrachloride, there was no evidence of effects of clear clinical significance on the liver function of workers exposed to carbon tetrachloride at the levels indicated.