ERYTHROSINE
EXPLANATION
Erythrosine was evaluated for an acceptable daily intake by
the Joint FAO/WHO Expert Committee on Food Additives at its eighth,
thirteenth, eighteenth, twenty-eighth and thirtieth meetings (Annex
1, references 8, 19, 35, 66 and 73). Toxicological monographs were
published after the thirteenth, eighteenth, twenty-eighth and
thirtieth meetings (Annex 1, references 20, 36, 67 and 74). At its
eighteenth meeting the Committee allocated an ADI of 0-2.5 mg/kg
bw; this was reduced at the twenty-eighth meeting to 0-1.25 mg/kg
bw and made temporary following observations that erythrosine
produced effects on thyroid function in short term studies in rats
and that, in long-term studies, male rats receiving 4% erythrosine
in the diet developed thyroid tumours. At the thirtieth meeting,
the Committee reduced the temporary ADI to 0-0.6 mg/kg bw, based on
studies of the biochemical effects of erythrosine on thyroid
hormone metabolism and regulation and required further data from
pharmacokinetic studies relating the amount of absorption to the
amount ingested, which would enable a correlation to be established
between blood/tissue levels of erythrosine and effects on the
thyroid.
Since the previous evaluation, additional data have become
available and are summarized and discussed in the following
monograph addendum.
Observations in man
Thirty normal men were divided into three groups and were
given erythrosine orally (in capsules) for 14 days at doses of 20,
60 or 200 mg/day. Assays for serum T4, T3, reverse T3, T3-
charcoal uptake, thyrotropin (TSH), protein bound iodine (PBI),
total iodide and total urinary iodide excretion were carried out on
days 1, 8 and 15; TRH test were performed on days 1 and 15.
There were no significant changes in serum T3, T4, rT3 and
T3-uptake in any group. In the top dose group (200 mg/day), the
mean basal serum TSH concentration increased from 1.7 ± 0.1 on day
1 to 2.2 ± 0.1 µU/ml on day 15 (p< 0.05) and the mean peak TSH
increment after TRH increased from 6.3 ± 0.5 to 10.5 ± 1.0 µU/ml
(p< 0.05). There were no significant changes in basal or peak TSH
responses at the two lower dose levels. Significant dose-related
increases in serum total iodide and PBI concentrations occurred in
all three groups and significant dose-related increases in urinary
iodide excretion occurred in the 60 and 200 mg/day dose groups.
These data were taken to indicate that the increase in TSH
secretion was related to the effect of increased serum iodide
rather than a direct effect of erythrosine on thyroid hormone
secretion or peripheral metabolism (Gardner et al., 1987).
The statistical design and interpretation of the preceding
study (Gardner et al., 1987) has been re-evaluated independently
in relation to the effects on basal TSH concentration and maximum
TSH increment after TRH provocation. With respect to basal TSH, it
was suggested that there was no statistical evidence for variation
due to treatment over the dose range studied when appropriate
statistical methods were used to control for apparent initial
differences among treatment groups. The maximum TSH increment
following TRH provocation did show a slight but significant
increase in the top dose group (200 mg/day) only (Crump & Farrar,
1987).
In a study designed to determine whether relatively small
supplementary amounts of iodine in the diet would affect thyroid
function, normal, euthyroid human subjects received 250, 500 or
1500 µg iodine daily for 14 days; the doses were selected to
correspond to the amounts of iodine that might be bioavailable from
the doses of erythrosine used in the study by Gardner et al.,
(1987). Following administration of 1500 µg/day there were small
but significant decreases in serum T4 and T3 concentrations, a
small compensatory increase in serum TSH concentrations and in the
TSH response to TRH. However, all values remained within the normal
range. In contrast, no changes occurred following daily
administration of 250 or 500 µg I2 (Paul et al., 1987).
COMMENTS
Additional human studies confirmed that erythrosine is poorly
absorbed. The data did not indicate the mechanism by which
erythrosine exerted its effect on the thyroid; however, it appeared
that inorganic iodine per se was not the causative agent. The
no-effect-level with respect to thyroid function in man was 60 mg
per person per day (equivalent to 1 mg/kg bw/day). The effect on
thyroid function detected at a higher dose level of 200 mg per
person per day was a small change in thyrotropin responsiveness to
thyrotropin releasing hormone.
The pharmacokinetic studies required by the previous Committee
were not forthcoming, therefore it was decided to extend the
temporary acceptable daily intake pending the results of such
studies.
EVALUATION
Level causing no toxicological effect
Man: 60 mg/day (approx. 1 mg/kg bw/day) (Based on effects on
thyroid metabolism in a 14-day study).
Estimate of temporary acceptable daily intake for man
0-0.05 mg/kg bw.
Further work or information
Required (by 1990)
Pharmacokinetic studies which relate the amount of absorption
to the amount ingested which would enable a correlation to be
established between blood/tissue levels of erythrosine and effects
on the thyroid, and which may elucidate the mechanisms of thyroid
effects.
REFERENCES
Crump, K.S. & Farrar, D.B. (1987). Effects of erythrosine on basal
and TRH-stimulated TSH levels: Statistical re-evaluation of data
from Gardner et al. (1986). Unpublished report of Clement
Associates Inc., Washington, DC. Submitted to WHO by Certified
Color Manufacturers Association Inc.
Gardner, D.F., Utiger, R.D., Schwartz, S.L., Witorsch, P., Meyers,
B., Braverman, L.E. & Witorsch, R.J. (1987). Effects of oral
erythrosine on thyroid function in normal men. Toxicol. Appl.
Pharmacol., 91, 299-304.
Paul, T., Meyers, B., Witorsch, R.J., Pino, S., Chipkin, S.,
Ingbar, S.H. & Braverman, L.E. (1987). The effects of small
increases in dietary iodine on thyroid function in euthyroid
subjects. Metabolism (in press).