Chemistry Reference
In-Depth Information
TABLE 3 Matrix of BINWOE Determinations for
Intermediate or Chronic Simultaneous Oral
Exposure to Chemicals of Concern
6.3.1 Direction of Interaction
The direction of interaction is predicted to be less
than additive based on a study in orally exposed chil-
dren indicating a protective effect of zinc on the hemato-
logical effects of lead (Chisolm, 1981). This is supported
by several intermediate-duration oral studies in rats
that show supplemental zinc protects against a number
of hematological effects of lead related to heme synthe-
sis, particularly at higher lead doses (Cerklewski and
Forbes, 1976; Flora
et al.
, 1982). The evidence for zinc
inhibition of lead hematotoxicity is clear and toxicologi-
cally signifi cant and is supported by clear mechanistic
understanding that excess zinc protects and reactivates
lead-inhibited ALAD (delta-aminolevulinic acid dehy-
dratase), decreases the absorption and tissue distribu-
tion of lead, and may induce proteins that sequester lead
and donate zinc to ALAD and for other tissue needs.
Effect of
On toxicity of
Lead
Manganese
Zinc
Copper
Lead
=IIICii n
=IIB h
=IIIC p
Manganese
>ICii n
? h
? p
>IIB2ii h
Zinc
<IB n
? n
<IB p
<IA h
Copper
<IC n
? n
<IIA h
<IB h
n, Neurological; h, hematological; p, hepatic. Direction of interac-
tion: =, additive; >, greater than additive; <, less than additive; ?,
indeterminate. Mechanistic understanding: I, clear; II, inferred; III,
unclear. Toxicologic signifi cance: A, clear; B, inferred; C, unclear.
Modifying factors: 2, different exposure duration or sequence than
anticipated; ii, different route of exposure than anticipated.
6.3.2 Mechanistic Understanding
the compounds listed in the row headings. For exam-
ple, the classifi cation for the effect of zinc on the
toxicity of lead is given in the fi rst column (lead) of
the third row (zinc). Similarly, the classifi cation for
the effect of copper on the toxicity of zinc is given
in row four (copper) column three (Zn). Binary clas-
sifi cations starting with an “=” indicate an additiv-
ity; those starting with a “>” indicate a greater than
additive interaction; and those starting with a “<”
indicate a less than additive interaction.
The qualitative WOE matrix may then be used as
a tool to quantify the risk assessment for a particular
site. The quantitative BINWOE can have an absolute
value of 0 to 1, with 1 indicating the highest degree
of confi dence in the assessment. Ultimately, this WOE
method can be used so as to modify the HI and include
the role of chemical interactions (ATSDR, 2001a, De
Rosa
et al.
, 2002; Mumtaz and Durkin, 1992). Improve-
ments in assessing human health risks from chemical
mixtures can only come about by reducing inherent
uncertainties in risk assessment methods. This will
require an understanding of how chemicals behave in
biological systems, as well as explaining their collective
mechanisms of action.
When performing an exposure-based assessment
of joint toxic action of the mixture, the BINWOEs
developed for the endpoints of concern can be used
qualitatively to predict the impact of interactions. An
analysis to evaluate neurological, hematological, and
hepatic effects of varying pairs of lead (Pb), manganese
(Mn), zinc (Zn), and copper (Cu) yielded the follow-
ing WOE matrix (Table 3). The BINWOE for the hema-
tological effect of zinc on lead is <IA. The qualitative
interpretation will be as follows:
A characteristic and sensitive effect of lead is the inhi-
bition of ALAD, a zinc-containing enzyme in the heme
synthesis pathway. Zinc protects the enzyme from inac-
tivation by lead
in vivo
and
in vitro
(Abdulla
et al.
, 1979;
Mauras and Allain, 1979), as assayed directly or by the
appearance of greater amounts of ALA (delta-aminole-
vulinic acid) in the urine. Supplemental zinc decreased
the gastrointestinal absorption of lead and decreased
blood, bone, liver, kidney, and spleen concentrations of
lead in rats in intermediate-duration studies (Cerklewski
and Forbes, 1976; El-Gazzar
et al.
, 1978; Flora
et al.
, 1982;
1989). This effect was seen at higher, but not lower, doses
and was not seen in humans at lower doses of both met-
als than those used in the rat studies. The evidence in
general suggests that oral coexposure to zinc at levels
signifi cantly above essentiality decreases lead absorption
and body burden at higher lead exposures. Zinc induces
a metallothionein that has been shown to sequester lead
in vitro
, protecting against its cytotoxicity (Goering and
Fowler, 1987; Liu
et al.
, 1991). A metallothionein-like pro-
tein in erythrocytes binds lead
in vitro
and was present
in higher concentrations in lead-exposed workers than
in controls. This protein was also present at exception-
ally high levels in a worker with very high blood lead
(180
g/dL), but no signs of lead poisoning, compared
with another worker with high blood lead (160
µ
g/dL)
who was symptomatic (Church
et al.
, 1993a; 1993b). An
acidic, soluble lead-binding protein in erythrocytes (and
brain and kidney) that normally binds zinc is postulated
to attenuate lead toxicity to ALAD through lead binding
and zinc donation (Fowler, 1998). The preceding mecha-
nistic data indicate that under conditions in which an
interaction occurs, the effect of zinc on the hematological
toxicity of lead will be less than additive.
µ
