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Toxicological information

Basic toxicokinetics

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Administrative data

Endpoint:
basic toxicokinetics in vivo
Type of information:
experimental study
Adequacy of study:
supporting study
Study period:
June 1, 1990 - May 29, 1991
Reliability:
2 (reliable with restrictions)

Data source

Reference
Reference Type:
study report
Title:
Unnamed
Year:
1991

Materials and methods

Objective of study:
other: distribution; excretion
Test guideline
Qualifier:
no guideline followed
Principles of method if other than guideline:
Groups of male Fischer-344 rats (10 rats/group) were exposed to feed containing either 0, 10, 30, or 100 ppm lead (in the form of lead acetate, lead oxide, lead sulfide, or Alaskan lead ore concentrate) for 30 days. Relative bioavailability of lead was assessed by measuring cumulative lead uptake in femur bone and excretion of delta-aminolevulinic acid (ALA) in urine on day 23 of exposure. Lead concentration was also measured in blood samples taken prior to exposure on day 0 and during exposure on days 7, 14, and 21.
GLP compliance:
no

Test material

Constituent 1
Reference substance name:
Lead oxide
EC Number:
215-626-1
EC Name:
Lead oxide
IUPAC Name:
Lead oxide
Constituent 2
Reference substance name:
Lead sulfide
IUPAC Name:
Lead sulfide
Constituent 3
Reference substance name:
Alaskan lead ore concentrate
IUPAC Name:
Alaskan lead ore concentrate
Constituent 4
Reference substance name:
Lead di(acetate)
EC Number:
206-104-4
EC Name:
Lead di(acetate)
Cas Number:
301-04-2
IUPAC Name:
lead (II) acetate trihydrate
Details on test material:
All test chemicals were supplied by the United States (US) National Toxicology Program through Radian Corporation.

The particle size distributions of the Alaskan lead ore concentrate, lead sulfide, and lead oxide were determined by sieving 100 g samples of the material through a stack of 8-inch US Standard Sieves. The material retained on each sieve was weighed and reported as percent of the total material recovered from the sieves. Approximately 90.33, 97.6, and 99.34% of Alaskan lead ore concentrate, lead sulfide, and lead oxide were retained, respectively. Lead acetate trihydrate was ground in a mortar and pestle in a nitrogen atmosphere to minimize water uptake and a -400 mesh fraction was collected by sieving the ground material through a 400-mesh US Standard Sieve.

Each compound was dried and subjected to quantitative analysis. For lead acetate, the dried material was assayed at 65.4% lead by weight, and this value was used in formulating feed dosages. For lead oxide and lead sulfide, the average assay results were 93.0% and 80.2% lead by weight, respectively. For the Alaskan lead ore concentrate, the dried material was sieved through a 400-mesh sieve and the fraction with particles less than 38 microns was assayed and used in feed preparations. The average assay value for the concentrate used in formulating feed dosages was 61.1% lead by weight.
Radiolabelling:
no

Test animals

Species:
rat
Strain:
Fischer 344
Sex:
male
Details on test animals or test system and environmental conditions:
TEST ANIMALS
- Source: Charles River Laboratories (Raleigh, North Carolina, United States).
- Age at study initiation: Approximately 38 days old.
- Housing: Individual polycarbonate cages with alpha-cellulose AlphaDri bedding.
- Individual metabolic cages: Yes, glass Roth-type metabolism chambers for collection of urine on day 23 of exposure.
- Diet: NRC-AIN-76A diet, ad libitum.
- Water: Filtered, deionized water.
- Acclimation period: 7 days.

IN-LIFE DATES: From: June 1, 1990; To: May 29, 1991

Administration / exposure

Route of administration:
oral: feed
Vehicle:
unchanged (no vehicle)
Details on exposure:
Test chemicals were mixed with feed flour and then blended with clean feed. Each formulation was analyzed for dose verification, and feed consumption was measured at weekly intervals.
Duration and frequency of treatment / exposure:
Animals ate dosed feed for 30 days.
Doses / concentrations
Remarks:
Doses / Concentrations:
0, 10, 30, or 100 ppm of lead in the form of either lead acetate, lead oxide, lead sulfide, or Alaskan lead ore concentrate.
No. of animals per sex per dose / concentration:
10
Control animals:
yes, plain diet
Details on study design:
Animals were ordered by weight during the acclimation period. Extra animals received in each shipment were removed by alternately discarding the lightest and heaviest animal until 40 animals remained. Animals were divided in order of ascending weight into ten sets of four animals each. One animal from each set was randomly assigned to each treatment group so the average weight and distribution of weights in each treatment group were the same.
Details on dosing and sampling:
On the first day of dosing (day 0), each animal was weighed and a blood sample taken. The food jar in each animal's cage was then replaced with a pre-weighed jar containing a known amount of spiked feed. At weekly intervals, each rat was weighed. Tail vein blood samples were obtained on days 7, 14, and 21 of exposure. Feed was replaced at weekly intervals and any remaining feed was weighed. On exposure day 23, rats were transferred to metabolic chambers for collection of urine. For lead oxide and lead sulfide studies, animals were kept in the metabolic chambers for 6 hours and were not given food or water during this time. This procedure did not provide sufficient urine from several animals for reliable ALA determination. For lead acetate and Alaskan lead ore concentrate, animals were provided dosed feed and water while in the chambers, where they were kept for up to 24 hours.

After 30 days of exposure, blood, brain, kidneys, and both femurs were removed from the animals. Femurs were dissolved in acid and analyzed for lead content by graphite furnace atomic absorption (GFAA). Blood lead concentrations were also measured by GFAA, with either deuterium arc background correction or Zeemann effect background correction. Delta-ALA was measured in urine as an index of lead exposure. Urine was acidified and absorbance at 556 nm was determined using a UV/Vis spectrophotometer.

Results and discussion

Toxicokinetic / pharmacokinetic studies

Details on distribution in tissues:
Concentrations of lead in femur were increased compared to controls (P < 0.05) for animals dosed with lead acetate and lead oxide at all three dose levels and for animals dosed with lead sulfide and Alaskan lead ore concentrate at the 30 and 100 ppm levels. Correlation coefficients indicated a high degree of correlation between lead dose and femur uptake in each case. Correlation coefficients (r-squared) were 0.9938 for lead acetate; 0.9953 for lead oxide; 0.9626 for lead sulfide; and 0.8733 for Alaskan lead ore concentrate. A feedback mechanism in the range of doses administered in this study was not observed for lead uptake. Such a mechanism would cause decreased uptake of lead when the total body burden of lead became high, and would be evidenced by a non-linear relationship between femur lead concentration and lead doase at high doses.

The authors reported substantial contamination of blood samples and stated that no conclusions could be made from the blood lead data in this study.

Although the methods indicated that brain and kidneys were removed from the animals after the exposure period ended, no relevant data or explanation of the use of these organs were provided in the report.
Details on excretion:
An increase in urinary ALA concentration was observed with increasing concentration of lead acetate in the feed. Compared to controls, the concentration of ALA in urine was 2.5-fold and 6.5-fold higher in the 30 ppm and 100 ppm lead acetate groups, respectively.

An increase in urinary ALA concentration was also observed with increasing concentration of lead oxide in the feed. Compared to controls, the concentration of ALA in urine was 5-fold higher in the 100 ppm lead oxide group.

There was no increase in urinary ALA concentration with increasing concentration of lead sulfide in the feed. ALA concentrations were lower over all dose groups compared to all dose groups of the other three test compounds. The average urinary ALA concentration for the control group for lead sulfide was approximately half the average ALA concentration for the control groups for the other three compounds, and no explanation for this was readily apparent.

For the Alaskan lead ore concentrate groups, there was no increase in concentration of urinary ALA in rats receiving 100 ppm lead in the feed compared to controls.

The authors stated that these results suggest that diets containing lead acetate and lead oxide provided sufficient lead in bioavailable form to cause increases in urinary ALA, and that the lead in the diets containing lead sulfide and the Alaskan lead ore concentrate was either not absorbed or was absorbed in a form not available for biochemical interactions normally associated with the toxic effects of lead.

Any other information on results incl. tables

There were no differences in feed consumption as a function of dose level for any of the test chemicals.

Applicant's summary and conclusion

Conclusions:
The authors concluded that diets containing lead acetate and lead oxide provided sufficient lead in bioavailable form to cause increases in urinary ALA, and that the lead in the diets containing lead sulfide and the Alaskan lead ore concentrate was either not absorbed or was absorbed in a form not available for biochemical interactions normally associated with the toxic effects of lead. They also concluded that, based on the uptake of lead into femurs, bioavailability was highest for lead acetate, intermediate for lead oxide, and lowest for lead sulfide and Alaskan lead ore concentrate. Femur uptake of lead was linearly related to dose for each compound studied, and lead uptake did not exhibit a feedback mechanism in the range of doses administered in this study.
Executive summary:

Groups of male Fischer-344 rats (10 rats/group) were exposed to feed containing either 0, 10, 30, or 100 ppm lead (in the form of lead acetate, lead oxide, lead sulfide, or Alaskan lead ore concentrate) for 30 days. Relative bioavailability of lead was assessed by measuring cumulative lead uptake in femur bone and excretion of delta-aminolevulinic acid (ALA) in urine on day 23 of exposure. Lead concentration was also measured in blood samples taken prior to exposure on day 0 and during exposure on days 7, 14, and 21. The authors reported substantial contamination of blood samples and stated that no conclusions could be made from the blood lead data in this study. The authors concluded that diets containing lead acetate and lead oxide provided sufficient lead in bioavailable form to cause increases in urinary ALA, and that the lead in the diets containing lead sulfide and the Alaskan lead ore concentrate was either not absorbed or was absorbed in a form not available for biochemical interactions normally associated with the toxic effects of lead. They also concluded that, based on the uptake of lead into femurs, bioavailability was highest for lead acetate, intermediate for lead oxide, and lowest for lead sulfide and Alaskan lead ore concentrate. Femur uptake of lead was linearly related to dose for each compound studied, and lead uptake did not exhibit a feedback mechanism in the range of doses administered in this study.