Appendix D - Dossier (PDF) - Tera

date: 20–JUL–2005
5. Toxicity Substance ID: 71–43–2
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Hsieh et al. (1988b) assessed the primary antibody response
to SRBC after benzene exposure. The number of PFCs in male
CD–1 mice receiving 40 and 180 mg/kg bw/d of benzene was
reduced, when expressed on either specific activity of
PFC/106 spleen cells or whole spleen basis. However, there
were more PFC per 106 spleen cells at the low level of
benzene. The titers of SRBC antibodies corresponded to the
numbers of PFC.
Following four weeks of oral benzene treatment via the
drinking water, the proliferative response of either
mitogen–stimulated or nonstimulated splenic lymphocytes were
elevated in male CD–1 mice at 8 mg/kg bw and depressed at 40
and 180 mg/kg bw/d (Hsieh et al. 1988b). This biphasic
alterations in proliferation of T– and B–lymphocytes was
observed using LPS, PWM, ConA and PHA.
In in vitro studies supernatants from splenic T–lymphocyte
cultures stimulated with ConA were assayed for Interleukin–2
(IL–2) content by their ability to enhance proliferation of
the murine T–helper cell line HT–2. Splenic IL–2 production
was suppressed in the 40 and 180 mg/kg bw treated benzene
groups (Hsieh et al. 1991).
In a further study, cell mediated immunity was measured in
splenic lymphocytes of 4 weeks orally exposed male CD–1 mice
by mixed–lymphocyte culture response to allogenic cells and
cytotoxic T–lymphocyte (CTL) activtiy to YAC–1 tumor cells.
Both immune reactions were inhibited at benzene doses of 40
and 180 mg/kg bw/d, but increased in the 8 mg/kg bw/d dose
group (Hsieh et al. 1988b).
Hsieh et al. (1988a) observed increased concentrations of
norepinephrine (NE) in the hypothalamus, medulla oblongata
and cerebellum of CD–1 mice fed continuously with drinking
water containing 31, 166 and 790 mg/l benzene for four
weeks. Dopamin (DA) concentrations increased significantly
in the hypothalamus and corpus striatum. Increases of
several catecholamine metabolites and the indoleamine
serotonin (5–HT) were seen in a number of brain regions. The
authors concluded that benzene induced increased rates of
synthesis and catabolism of neurotransmitters NE, DA, and
5–HT. Besides of direct toxic effects on the immune system,
the increases in brain catecholamines can act indirectly on
the immune system via hypothalamus–pituitary–adrenal axis.
Increased metabolisms of catecholamines can result in
increased adrenal corticosteroid levels.
Oral administration to mice at doses from 8 mg/kg bw/d, for
four weeks; induced increased catecholamine concentrations
of the brain, increased adrenocorticotropin (ACTH) and
corticosterone release into the blood (Hsieh et al. 1991).
An indirect action on the immune system via the
hypothalamus–pituitary–adrenal axis was supposed. The oral
studies did not include any data on behavioural dysfunctions
or morphological abnormalities.
Source: BP Chemicals Ltd LONDON;
German Rapporteur
Appendix D: Benzene SIDS Dossier
– 377/957 –