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Toxicological information

Exposure related observations in humans: other data

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Administrative data

Endpoint:
exposure-related observations in humans: other data
Type of information:
experimental study
Adequacy of study:
supporting study

Data source

Reference
Reference Type:
publication
Title:
Unnamed
Year:
1976

Materials and methods

Endpoint addressed:
basic toxicokinetics
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
The steady state kinetics of lead metabolism were studied in five healthy adult male volunteers using stable isotope tracers. Subjects lived in a hospital metabolic unit and ate constant low-lead diets. Their intake was supplemented each day with 79 to 204 ug of enriched 204Pb as lead nitrate, which was ingested with meals for 1 to 124 days. The concentration and isotopic composition of lead was determined in blood, urine, feces, diet, hair, nails, sweat, bone, and alimentary tract secretions by isotopic dilution mass spectrometry analysis.
GLP compliance:
no

Test material

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Tracers enriched with 204Pb (89% pure) or 207Pb (99.9% pure) as nitrate were obtained from Oak Ridge National Laboratories (Oak Ridge, Tennessee, United States).

Method

Ethical approval:
confirmed and informed consent free of coercion received
Details on exposure:
Subjects (Table 1) were fed diets constant in lead content and a supplement of lead isotope was ingested at each meal and with an evening snack. The subjects' total daily lead intake was designed to approximate their pre-study levels as estimated from two 5-day fecal collections analyzed before the administration of the supplement. A lead nitrate tracer enriched with 204Pb was usually used, but in three subjects, 207Pb was used for short periods of time as an additional tracer.

During the study the total content and isotopic composition of lead were measured in all pooled specimens of urine and feces which were collected continuously, in diets which were prepared in duplicate at weekly intervals, and in whole blood which was collected serially. Feces and urine were each combined into 5- to 10-day pools. Blood was collected in the morning from subjects who were fasting since the previous midnight. In long-term studies, lead was measured periodically in facial and total body hair, nails, induced sweat, saliva, and gastric, pancreatic, and biliary secretions. In addition, several bone biopsies were obtained from two subjects. Blood and facial hair was also collected during periods when subjects were not receiving the tracer or were not ingesting a constant lead diet.

Results and discussion

Results:
The isotope composition of the lead observed in the various tissues and fluids in the study can be understood in terms of a three-compartment model. Compartment one includes primarily blood and other tissues which are in rapid isotopic equilibrium with blood. Kinetic analysis of the data indicates that this compartment contains about 1.9 mg lead and receives isotopically-labeled lead from the gastrointestinal (GI) tract and unlabeled lead from the atmosphere. It exchanges lead with compartments two and three, and lead also moves from compartment one into the urine. Compartment two includes primarily soft tissues and possibly the more actively-exchanging parts of the skeleton. It contains approximately 0.6 mg lead and gives rise to hair, nails, and at least some alimentary tract secretions. Compartment three includes the skeleton and, therefore, most of the lead in the body. The mean life of lead in pool one was 36 days; in pool two the mean life varied from 30 to 55 days; in the third pool, it was much greater (around 10000 days).

The mean urinary excretion varied from 27 to 41 ug/day. From a comparison of the mean life and size of the first pool and the daily output of lead in urine, it was calculated that 54 to 78% of the lead leaving the blood each day passes out of the body in urine. The isotope composition of urinary lead closely resembled the composition of whole blood obtained during that time. An average of 2.0 to 2.4 ug of total lead was removed by blood drawing each day, representing about 4% of the daily output of lead from the first pool.

In contrast to urine, other bodily outputs of lead did not appear to be isotopically equilibrated with whole blood. For purposes of kinetic modeling, the origin of the various bodily outputs can be assigned to a common physiological pool, distinct from blood. Relatively little lead from this pool is returned to blood, and about 25% of the daily amount of lead leaving blood goes to this second pool.

The rate at which lead moves into the skeleton is taken as the difference between the rate of lead output from pool one and the sum of the lead outputs from pool one to pool two and to urine. The estimated movement of total lead from pool one to the skeleton was 9 ug/day for subject A, 5 ug/day for subject B, and 4 ug/day for subject D. An observation supporting the existence of a third pool is based on evidence indicating that lead moves from the skeleton to blood. After discontinuing ingestion of the lead tracer, its concentration in the blood does not decrease as rapidly as would be predicted from a two-pool model, but instead suggests that there is an internal, long-lived source of the tracer. A total of about 6 to 10 ug of lead was calculated to move from bone to blood each day.

Initially in the study, no tracer lead was excreted by the body into the feces because the source of these excretions was not yet labeled. After a few months of continuous tracer intake, bile and GI secretions contained appreciable amounts of tracer lead, and endogenous fecal secretion of tracer lead may have contributed up to a few micrograms per day to total fecal output of tracer. In two subjects (A and B), a second isotope tracer, 207Pb as nitrate, was administered for 10 days to differentiate between endogenous excretion of lead tracer and delayed passage of unabsorbed tracer. Ingestion of both tracers was discontinued at the same time. Fecal excretion of the second tracer was not detectable 20 days after it was discontinued, so excretion of the first tracer more than 20 days after ingestion was terminated was considered to represent endogenously excreted lead.

Applicant's summary and conclusion

Conclusions:
The authors concluded that a three-compartment model for lead metabolism is suggested from the data, and that there may be a difference between rodents and humans in the physiological handling of lead.
Executive summary:

The steady state kinetics of lead metabolism were studied in five healthy adult male volunteers using stable isotope tracers. Subjects lived in a hospital metabolic unit and ate constant low-lead diets. Their intake was supplemented each day with 79 to 204 ug of enriched 204Pb as lead nitrate, which was ingested with meals for 1 to 124 days. The concentration and isotopic composition of lead was determined in blood, urine, feces, diet, hair, nails, sweat, bone, and alimentary tract secretions by isotopic dilution mass spectrometry analysis. The isotope composition of the lead observed in the various tissues and fluids in the study can be understood in terms of a three-compartment model. Compartment one includes primarily blood and other tissues which are in rapid isotopic equilibrium with blood. Kinetic analysis of the data indicates that this compartment contains about 1.9 mg lead and receives isotopically-labeled lead from the gastrointestinal (GI) tract and unlabeled lead from the atmosphere. It exchanges lead with compartments two and three, and lead also moves from compartment one into the urine. Compartment two includes primarily soft tissues and possibly the more actively-exchanging parts of the skeleton. It contains approximately 0.6 mg lead and gives rise to hair, nails, and at least some alimentary tract secretions. Compartment three includes the skeleton and, therefore, most of the lead in the body. The mean life of lead in pool one was 36 days; in pool two the mean life varied from 30 to 55 days; in the third pool, it was much greater (around 10000 days). The mean urinary excretion varied from 27 to 41 ug/day. From a comparison of the mean life and size of the first pool and the daily output of lead in urine, it was calculated that 54 to 78% of the lead leaving the blood each day passes out of the body in urine. The isotope composition of urinary lead closely resembled the composition of whole blood obtained during that time. An average of 2.0 to 2.4 ug of total lead was removed by blood drawing each day, representing about 4% of the daily output of lead from the first pool. In contrast to urine, other bodily outputs of lead did not appear to be isotopically equilibrated with whole blood. For purposes of kinetic modeling, the origin of the various bodily outputs can be assigned to a common physiological pool, distinct from blood. Relatively little lead from this pool is returned to blood, and about 25% of the daily amount of lead leaving blood goes to this second pool. The rate at which lead moves into the skeleton is taken as the difference between the rate of lead output from pool one and the sum of the lead outputs from pool one to pool two and to urine. The estimated movement of total lead from pool one to the skeleton was 9 ug/day for subject A, 5 ug/day for subject B, and 4 ug/day for subject D. An observation supporting the existence of a third pool is based on evidence indicating that lead moves from the skeleton to blood. After discontinuing ingestion of the lead tracer, its concentration in the blood does not decrease as rapidly as would be predicted from a two-pool model, but instead suggests that there is an internal, long-lived source of the tracer. A total of about 6 to 10 ug of lead was calculated to move from bone to blood each day. Initially in the study, no tracer lead was excreted by the body into the feces because the source of these excretions was not yet labeled. After a few months of continuous tracer intake, bile and GI secretions contained appreciable amounts of tracer lead, and endogenous fecal secretion of tracer lead may have contributed up to a few micrograms per day to total fecal output of tracer. In two subjects (A and B), a second isotope tracer, 207Pb as nitrate, was administered for 10 days to differentiate between endogenous excretion of lead tracer and delayed passage of unabsorbed tracer. Ingestion of both tracers was discontinued at the same time. Fecal excretion of the second tracer was not detectable 20 days after it was discontinued, so excretion of the first tracer more than 20 days after ingestion was terminated was considered to represent endogenously excreted lead. The authors concluded that a three-compartment model for lead metabolism is suggested from the data, and that there may be a difference between rodents and humans in the physiological handling of lead.