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Epidemiological data

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Administrative data

Endpoint:
epidemiological data
Type of information:
experimental study
Adequacy of study:
key study
Study period:
July 1998
Reliability:
2 (reliable with restrictions)
Rationale for reliability incl. deficiencies:
other: see 'Remark'
Remarks:
Non-GLP. Invalid controls (tendency to high TSH values and urinary iodine) + overlapping of exposure ranges between the three exposed groups + unclear and inconstant inclusion criteria + few women and no hypothyroid persons + absence of data on microscopic changes: limits sensitivity. The later study by Braverman (in same section), from same production plant, is more robust and leads to a similar NOAEL.
Cross-reference
Reason / purpose:
reference to other study

Data source

Reference
Reference Type:
publication
Title:
Thyroid health status of ammonium perchlorate workers: a cross-sectional occupational health study
Author:
Lamm SH, Braverman LE, Li FX et al
Year:
1999
Bibliographic source:
JOEM, 1999, 41(4): 248-60

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

Reference
Name:
Unnamed
Type:
Constituent
Details on test material:
Not indicated.
In whole RSS, AP means Ammonium Perchlorate and SA designs Sodium Azide (control).

Method

Type of population:
occupational
Ethical approval:
not applicable
Details on study design:
METHOD OF DATA COLLECTION
- Type: Work history + Clinical tests

STUDY PERIOD: July 1998.
exposure period: not indicated, between 1989 (opening of the plant) and 1998, 40% workers exposed for >5 years.

WORKER POPULATION (AP and SA combined)
- AP plant in Cedar City, Utah, USA
- Age 20-56y
- Smoker/nonsmoker: not detailed, did not differ between AP and SA groups
- Total number of subjects at end of study: idem beginning

STUDY POPULATION
- Total population: 39
- Selection criteria: only 2 workers absent at time of study did not participate. Two workers with thyroid disease were included in low and mid-dose groups. However inclusion criteria depended on parameters (e.g., thyroid-ill persons excluded from tables on effects)
- Total number of subjects participating in study: 37 (14 in low-dose + 8 in mid-dose + 15 in high-dose)
- Sex: 35M+2F
- Mean age: 30y

COMPARISON POPULATION: Sodium azide
- Type: Control group: plant near the ammonium perchlorate plant
- Total population: 21
- Selection criteria: none
- Total number of subjects participating in study: 21
- Sex: 19M+2F
- Mean age: 35y

Due to the limitations in validity of the controls, comparisons were also made with respect to normal ranges.

HEALTH EFFECTS STUDIED
- Disease(s): thyroid disease + secondary effects
- Diagnostic procedure: determination of T3, T4, TSH; thyroid hormone binding ratio, free T4 index, thyroid peroxidase antibody titers, urine iodine, red and white blood cell and platelet counts
Exposure assessment:
measured
Details on exposure:
TYPE OF EXPOSURE:
Chronic, occupational, task-related, in three groups:
low-dose: handling of solutions/slurries
mid-dose: handling of limited amounts of dry substance with minor visible dust
high-dose: handling of large amounts of dry substance with significant visible dust

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

EXPOSURE LEVELS: see results table below

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

POSTEXPOSURE PERIOD: non-shift periods per cycle

Results and discussion

Results:
- T3, T4, red and white blood cell (total, neutrophiles, lymphocytes) and platelet counts, urine iodine, were all within normal limits
- TSH: some high values at high-dose, but same finding in control, suggesting no clear relationship with perchlorate
- Non-adverse increases in blood and urine perchlorate
- thyroid hormone binding ratio, free T4 index, thyroid peroxidase antibody titers: not perfectly within normal limits in exposed groups but lacked dose-relationship

see results table below
Confounding factors:
Low-detailed (no thiocyanate measure) but considered to have no relevant influence
Excess iodine supply excluded (except in sodium azide group)
Strengths and weaknesses:
Strength: assessment of absorbed dose and large variety of parameters
Weakness: very few women and no sensitive persons (hypothyroid), exposure assessed one time but some parameters assessed may relate to years of exposure, high TSH values in some controls and high-dose workers, no data on microscopic changes, inconstant inclusion criteria

Any other information on results incl. tables

Descriptive statistics of exposure and effects [min-max (median)] in workers exposed chronically to ammonium perchlorate or control (sodium azide)

Sodium azide (invalid controls) Perchlorate low-dose Perchlorate mid-dose Perchlorate high-dose
n# 21 12-14 8 14-15
Absorbed dose (mg perchlorate /shift)§ <0.16-4.3 (0.6) 0.4-9.4 (3.4) 3.1-28.1 (8.4) 12.7-68.7 (33.4)
Absorbed dose (mg AP/kg/day)§& NC NC NC 0.11-0.58 (0.28)
T4 µg/dL (5-11) 4.6-9.9 (6.8) 4.0-10.6 (6.9) 5.4-8.9 (7.5) 4.4-8.6 (7.3)
T3 ng/dL (87-178) 113-169 (143) 96-174 (159) 120-181 (148) 108-192 (150)
TSH mU/L (0.45-4.5) 0.7-8.4 (2.8) 1.2-4.5~ (2.5) 0.8-4.3 (2.2) 0.7-8.2 (2.8)

#: depended on parameter assessed; §: based on urinary perchlorate excretion;

&: calculated by RSS/CSR author assuming BW of 70kg, 3 shifts/6 days, conversion between perchlorate and AP (x 1.18);

~: excluding one worker with Grave's disease before employment

all values are min-max (median); NC: not calculated (useful at top-dose only)

italics: laboratory's reference range

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 0.21 mg AP/kg/day (25%tile of absorbed exposure in the most exposed group, representing at least 25 workers).
Executive summary:

In this study, 35 male and 2 female workers exposed chronically to perchlorate, mainly by respiratory route, were investigated for perchlorate exposure level (based on air, serum and urine perchlorate concentrations) and a whole range of thyroid and hematological endpoints.

T3, T4, red and white blood cell and platelet counts, urine iodine, were all within normal limits at up to individual absorbed doses of 69 mg perchlorate/shift, for a 60thexposure percentile of 5 years (chronic exposure), for 42h/week. TSH was above normal limits (up to 8.2 mUI/L) in some of the 15 high-dose workers, with an estimate of 7 persons having TSH above the cut-off of 3 mUI/L, based on reported statistical data. However, the same observation (TSH up to 8.4 mUI/L) was made in the control group exposed to sodium azide in the same conditions, meaning that a causal relationship with perchlorate exposure seemed unlikely. Some other parameters were not perfectly within normal limits in exposed groups but lacked dose-relationship (thyroid hormone binding ratio, free T4 index, thyroid peroxidase antibody titers). Non-adverse increases in blood and urine perchlorate levels were noted.

In this study, controls were slightly suboptimal due to the aforementioned abnormal TSH values and also the high urinary iodine excretion (211 +/- 120 µg/g creatinine). However interpretation was possible by comparison with normal ranges.

In a worst-case approach, excluding the (estimated) 7 high-dose perchlorate workers (out of 14) with unexplained high TSH and hypothesizing that these were the most exposed ones, it was considered reasonable to retain not the median or maximal absorbed exposure, but the 25%tile of absorbed exposure in this high-dose group (i.e. the upper bound of the absorbed dose, representing about 3-4 high-dose workers + all 8 mid-dose workers + all 14 low-dose workers = at least 25 workers) as the NOAEL. The latter was therefore 24.68 mg perchlorate/shift as a NOAEL for an exposure of 42h/week, corresponding to 12.34 mg perchlorate/day i.e. 0.176 mg perchlorate/kg/day (assuming a 70-kg worker), equivalent to 0.21 mg AP/kg/day.