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Toxicological information

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Administrative data

direct observations: clinical cases, poisoning incidents and other
Type of information:
experimental study
Adequacy of study:
key study
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: Acceptable, well-documented publication, adequate for assessment

Data source

Reference Type:
A comparative study of the effects of carbon monoxide and methylene chloride on human performance
Putz VR, Johnson BL, Setzer JV
Bibliographic source:
J Environ Pathol Toxicol 2, 97-112

Materials and methods

Study type:
study with volunteers
Endpoint addressed:
acute toxicity: inhalation
Test guideline
no guideline available
Principles of method if other than guideline:
See below for the method
GLP compliance:
not specified

Test material

Constituent 1
Chemical structure
Reference substance name:
EC Number:
EC Name:
Cas Number:
Molecular formula:
Details on test material:
The MeC used for exposure was of spectrographic grade with a minimum purity of 99.5 percent.


Type of population:
The purpose of this investigation was to determine whether similar carboxyhemoglobin (COHb) values obtained from inhaling carbon monoxide or methylene chloride have the same behavioral effects. The effects were assessed by the performance of 12 humans on a visual-manual, dual-task, and an auditory vigilance task. In the present study a condition of CO exposure and a condition of methylene chloride exposure were studied along with a third condition of no-exposure, i.e., a control condition.

Six male, and six non-pregnant females between 18-40 yrs of age (non-smokers) with normal or corrected vision were recruited by advertisement. Each participant was given a pre-study medical examination, including a resting ECG, by a physician. Upon the recommendation by the physician and evidence of a work history that did not involve prior solvent exposure, the candidate was accepted. Five consecutive hours were scheduled for the behavioral testing on three separate days at 7-day intervals in order to allow any residual effects of methylene chloride or CO to dissipate. Each participant was paid at the rate of $6/hr for 15 hours of testing and the 1-hour physical exam. All participants were informed of their rights and given consent forms to complete as approved by the NIOSH Human Subject Review Board. All procedures were in accordance with the Ethical Principles in the Conduct of Research (1973) published by the American Psychological Association.
Ethical approval:
confirmed and informed consent free of coercion received
Route of exposure:
Reason of exposure:
Exposure assessment:
Details on exposure:
The experimental plan called for a 4-hour consecutive exposure duration. In an attempt to achieve a body burden level equivalent to an 8-hour exposure at 100 ppm, the concentration of methylene chloride was doubled to 200 ppm for the 4-hour exposure. The expectation was that this would produce about 5 percent COHb during the fourth hour of exposure. For the CO condition a 70-ppm concentration should also produce about 5 percent COHb during the fourth hour of exposure. A repeated measure design using each subject as his or her own control was employed. The three exposure conditions were completely counter-balanced with one exposure condition per day with a 7-day interval, to neutralize order, and carry over effects. The counterbalancing scheme was replicated twice. Two subjects were run simultaneously in a yoked replication of the counterbalancing scheme.
The effects were assessed by the performance of 12 humans on a visual-manual, dual-task, and an auditory vigilance task. Within each task, two levels of difficulty were defined to allow for a treatment level and task difficulty interaction. COHb levels were determined for each subject from the two blood samples taken before and after exposure.

The 4-hour exposure was divided into three 80-min blocks for each participant. Within each block, four main time periods were defined according to the activity; dual-task, auditory vigilance, dual-task and rest. The first time period lasted 16 min and consisted of eight 1-min dual-task trials per subject. Each person performed for 2 min then paused for 2 min. At 18 min into the block, the participants performed a 30-min auditory vigilance task, which was followed by a breath sample which required about 5 or 6 min for the two subjects. The subjects then performed another 16 min on the dual-task activity. The remaining 8 or 9 min of the 80-min block were for rest. This same sequence was repeated three times for the 240-min of exposure each of the 3 exposure days. This design provided a dose-response relation for each individual beginning at a zero concentration at the beginning of the exposure period, and peaking at the TLV concentration, which was approached and maintained for approximately 1 hour during the last hour of the exposure period. In order to analyze for possible interactions between task difficulty levels, ex¬posure time, and exposure conditions for the response vectors, a multi¬variate analysis of variance test was used.

After confirming that the subject was not experiencing headache, nausea, dizziness, eye, nose, or throat irritation, or any subjective symptom, a pre-exposure finger prick blood sample was obtained for subsequent COHb analysis. A second finger prick blood sample was also taken at the end of the exposure period. Alveolar breath samples were collected in 6-I plastic bags using the 20-sec breath holding technique every hour, during and after exposure for a total of five per exposure condition. Since the study was concerned with levels of MeC and CO sufficient to produce equivalent levels of COHb, methylene chloride breath concentrations were not obtained.

The main performance test was an eye-hand coordination task performed concurrently with peripheral brightness monitoring. The eye-hand task required the participant to manipulate a small hand control lever in order to position an oscilloscope beam in the center of the scope face.The degree to which the participant tracked the forcing function by compensatory movements of the control level served as an index of eye-hand coordination.

The task which was performed simultaneously with the tracking task, producing the dual-task arrangement, involved monitoring peripheral stimuli for the occurrence of a signal. The participant would respond to the signal, which was an increase in the light intensity of two peripherally mounted lights, by pressing a response switch. The dual-task arrangement under moderate to high levels of difficulty required sustained attention divided between two sources.
Following testing on the dual-task activity, an auditory vigilance task was conducted for 30 min. Subjects listened by earphone to a train of pulses of white noise. At random intervals with a probability of p = 0.20 a slightly less intense or more intense pulse was inserted. The less intense pulse, called the signal, was to be reported by pressing a hand-held button.

All performance tests were automated through use of a laboratory digital computer to ensure reliability and to eliminate direct subject-experimenter interaction. In addition, the experiment was conducted as a double-blind to reduce bias.

Results and discussion

Clinical signs:
The performance measures used to assess both methylene chloride and CO exposures indicated a decrease in the speed and precision of psychomotor performance, which is believed to be an indication of a temporary decrease in the level of central nervous system activation.
Results of examinations:
The results from the performance tests suggested that both methylene chloride and CO in concentrations sufficient to produce approximately 5 percent COHb have adverse behavioral effects which are similar in terms of the direction of the effect, but may vary with certain tasks in the magnitude of the effect. In general, the deteriorating effects of methylene chloride and CO were evident only under task conditions that were defined as being difficult or demanding. Of course, the validity of the behavioral results was depen¬dent on achieving the desired exposure concentrations. Both methylene chloride and CO produced the desired COHb levels of around 5 percent.

Chamber levels: For the methylene chloride condition 200 ppm of methylene chloride was desired, while an average of 195 ppm was actually recorded.

Breath Levels: For both the methylene chloride and CO treatments the CO concentration in expired air increased fairly rapidly in the first 2 hours with a slow leveling off after the third hour.
Carboxyhemoglobin (COHb) levels (determined mean values pre- and post-exposure respectively): control group, 1.6 percent (s = 0.45) and 1.4 percent (s = 0.48); CO treatment condition 1.5 percent (s = 0.44) and 4.85 percent (s = 0.47); methylene chloride treatment condition 1.35 percent (s = 0.38) and 5.1 percent (s = 0.48).

Performance Exposure Data: Five measures of dual-task performance were simultaneously analyzed in a multivariate analysis of variance (MANOVA): tracking error, peripheral signal misses, false alarms, correct detections (hits) and peripheral light response time. A three-way interaction relating exposure condition, exposure time and task difficulty was significant in the MANOVA. The significant variance was primarily manifested in the measures of tracking error and peripheral light response time.
Tracking performance: Tracking performance began to deteriorate for both the methylene chloride and CO exposure after hour 2, compared with the control.
Visual-Peripheral Data: For the visual-peripheral component of the dual-task, the CO exposure resulted in a decline in the mean response time by 11 percent (0.1 sec), while the methylene chloride exposure produced a decrement of 17 percent (0.15 sec), compared to the control.
Auditory Monitoring Data: For all subjects, overall conditions, 59 percent of the signal tones were correctly detected within 2.5-secs of their presentation. The control conditions averaged about 63 percent correct, while the CO and methylene chloride conditions dropped from that level to around 40 percent correct between the third and fourth hour of exposure.

Applicant's summary and conclusion