Sodium perchlorate

Epidemiological data

Administrative data

Endpoint:

epidemiological data

Type of information:

migrated information: read-across from supporting substance (structural analogue or surrogate)

Adequacy of study:

key study

Study period:

January - April 2004

Reliability:

2 (reliable with restrictions)

Rationale for reliability incl. deficiencies:

other: see 'Remark'

Remarks:

Non-GLP. Invalid controls (tendency to high TSH, urinary iodine and thyroid volume) but comparison with normal ranges possible; absence of women or hypothyroid persons; thyroid volume as a surrogate for possible microscopic changes; non-communication of min and max thyroid hormone values: limits the sensitivity/specificity of the study. Some results missing (blood cell counts, T3 uptake). However this chronic exposure study can be used to derive a DNEL by using the standard intraspecies Assessment Factors of 5/10 (worker/general population) to account for the slightly suboptimal variability of its exposed population.

Cross-reference

Reason / purpose for cross-reference:

reference to other study

Data source

Reference

Reference Type:

publication

Title:

The effect of perchlorate, thiocyanate, and nitrate on thyroid function in workers exposed to perchlorate long-term

Author:

Braverman LE, He X, Pino S et al

Year:

2005

Bibliographic source:

JCEM. 2005. 90(2):700-6.

Materials and methods

Study type:

cross sectional study

Endpoint addressed:

repeated dose toxicity: inhalation

Test guideline

Qualifier:

no guideline required

GLP compliance:

no

Test material

Test material information

Constituent 1

Reference substance name:

Ammonium perchlorate

EC Number:

232-235-1

EC Name:

Ammonium perchlorate

Cas Number:

7790-98-9

IUPAC Name:

ammonium perchlorate

Details on test material:

Not indicated
In whole RSS, AP means Ammonium Perchlorate.

Method

Type of population:

occupational

Ethical approval:

not applicable

Details on study design:

METHOD OF DATA COLLECTION
- Type: Work history + Clinical tests

STUDY PERIOD: January - April 2004.
exposure period: not indicated, between 1989 (opening of the plant) and 2004, 50% workers exposed for >5.9 years.

POPULATION (AP and control combined)
- Smoker/nonsmoker: both, frequency did not differ between AP and control groups; thiocyanate was measured as confounder
- Total number of subjects at end of study: idem beginning

STUDY POPULATION
- AP plant workers in Cedar City, Utah, USA
- Total population: 40
- Selection criteria: none (voluntary participation)
- Total number of subjects participating in study: 29
- Sex: all male
- Mean age: 33.6y

COMPARISON POPULATION:
- Type: volunteer community controls (not in the plant)
- Selection criteria: none (voluntary participation)
- Total number of subjects participating in study: 12
- Sex: all male
- Mean age: 39.5y

There was additionally a comparison between pre-exposure and exposure.
Due to the limitations in validity of the controls, comparisons were also made with respect to normal ranges. However, this is very limited because of anon-communication of group min/max values for each effect.

HEALTH EFFECTS STUDIED
- Disease(s): thyroid disease + secondary effects
- Diagnostic procedure: determination of T3, T4, TSH, radioactive iodine uptake, T3 uptake, free T4 index, thyroglobulin, thyroid volume; urine iodine, serum biochemistry for kidney and liver function, blood cell counts

Exposure assessment:

measured

Details on exposure:

TYPE OF EXPOSURE:
Chronic, occupational, task-related, not separated in groups but as a continuous exposure level distribution
Handling operations not indicated.

TYPE OF EXPOSURE MEASUREMENT:
- Biomonitoring: urine and serum perchlorate levels used to determine actual absorbed dose (systemic exposure)

EXPOSURE LEVELS: around 0.01 to >1.0 (median: 0.33) mg perchlorate/kg/shift i.e. 100-fold variability among the 29 exposed workers

EXPOSURE PERIOD: three 12h-shifts per cycle of 6 days (42h/week)

POSTEXPOSURE PERIOD: non-shift periods per cycle

Results and discussion

Results:

- no relevant effect on T3, T4, TSH, thyroid volume, thyroglobulin and urinary iodine
- free T4 index above normal limits in all groups and increased during exposure: not relevant as this is opposite to the expected effect of perchlorate
- non-adverse increases in blood and urine perchlorate and non-significant decrease in radioactive iodine uptake; increased uptake during absence of exposure (compensation)
- unaffected kidney and liver function (data not given)
- no comments on blood cell counts and T3 uptake results

see results table below

Confounding factors:

Measurement of iodine uptake inhibitors thiocyanate and nitrate; no significant difference.
Excess iodine supply excluded (except in control group)

Strengths and weaknesses:

Strength: assessment of absorbed dose and large variety of parameters; chronic exposure

Weakness: no women and no sensitive persons (hypothyroid), exposure assessed one time but some parameters assessed may relate to years of exposure, invalid controls (tendency to high TSH values, thyroid volume and urinary iodine), no data on microscopic changes, interpretation limited due to non-communication of min and max values (impossible to determine if values step outside normal ranges). Given the 100-fold variability of exposure in workers, effects should have been plotted against exposure level instead of comparisons with controls.

Any other information on results incl. tables

Exposure and effects [mean (median)] in workers exposed chronically to ammonium perchlorate or in community control volunteers

	Controls (invalid)	AP workers before exposure	AP workers during exposure
n	12	29
Serum perchlorate (µg/L)	0.0 (0.0)	2.0 (0.0)	838 (359)**
Absorbed dose mg perchlorate/kg/shift	0	NC	NC (0.33)
Absorbed dose mg AP/kg/day &	0	NC (0.20)
Radioiodine uptake %	14.4 (14.5)	21.5 (18.4)**	13.5 (13.1)
T4 µg/dL (5-11)	7.5 (7.3)	7.7 (8.0)	8.3 (8.6)
T3 ng/dL (87-178)	130 (130)	134 (138)	147 (147)
TSH mU/L (0.45-4.5)	3.1 (3.0)	2.0 (1.5)*	2.2 (1.8)

§: based on serum and urine perchlorate levels; all values are mean (median); NC: not calculated

&: calculated by RSS/CSR author by conversion between perchlorate and AP (x 1.18);

italics: laboratory's reference range in Lamm 1999 (see other RSS in same section)

*,**: p<0.05 or 0.01 vs. controls

Applicant's summary and conclusion

Conclusions:

At the exposure levels assessed and based on the parameters investigated, ammonium perchlorate had no adverse effect in workers exposed chronically for several years mainly by inhalation. The NOAEL retained by RSS/CSR author was 0.20 mg AP/kg/day, the median exposure level over all investigated workers.

Executive summary:

In this study, 29 male workers exposed chronically to perchlorate, mainly by respiratory route, were investigated for perchlorate exposure level (based on serum and urine perchlorate concentrations) and a whole range of thyroid and hematological and biochemical endpoints.

When comparing with normal limits, it could be concluded that no effect on T3, T4 and TSH, thyroid volume (as a surrogate for thyroid histological changes), thyroglobulin and urinary iodine excretion occurred at a median absorbed dose of 0.167 mg perchlorate ion/kg/day, over 5.9 years (median: chronic exposure) for 42h/week. Free T4 index was above normal limits in all groups but this is the opposite to the expected effect of perchlorate. Exposure of exposed workers was demonstrated by decreased radioiodine uptake and the detectable serum and urinary perchlorate levels (non-adverse effects).

In this study the male controls with were considered invalid for interpretation due to a tendency to high TSH, thyroid volume and more particularly urinary iodine. However interpretations were possible by comparison with normal ranges.

In workers, the equivalent AP exposure level, calculated as 0.20 mg AP/kg/day, was a NOAEL for 42h/week exposure since decreased radioiodine uptake is not considered an adverse effect.