Chemistry Reference
In-Depth Information
signifi cance of biomarkers is needed. ESOD levels may
occur as a result of excessive zinc intakes. Most prob-
ably, this is a result of interference by zinc with uptake
of copper, and the balance between zinc and copper is
of fundamental importance for the expression of this
effect (WHO/IPCS, 1998). For excessive iron intakes,
excessive transferrin saturation and excessive levels of
serum ferritin can be used as markers of iron overload
(Borch-Johnsen and Peterson-Grawé, 1995; Chapter
30). The clinical signifi cance of marginally increased
iron overload is still under discussion. Large excesses
like those occurring in persons with hemochromato-
sis are clearly of clinical importance. Homozygotes
for hemochromatosis are at several hundred fold
increased risk of liver cancer and an increased risk
of coronary heart disease (Bradbear
et al.
, 1985; Nied-
erau
et al.
, 1985; Chapter 30). Moderate levels of iron
overload may also be related to increased risks for
carcinogenicity in several organs, including the liver,
but such effects are not well documented. A relatively
large proportion of the population is heterozygotic for
the hemochromatosis gene and potentially at risk for
iron overload.
High selenium intakes may give rise to prolonged
plasma prothrombin time and increased ALAT (see
also Chapter 38).
TABLE 2 Principles Underlying Use of the Homeostatic
Model in Human Health Risk Assessment of EMs
(From WHO/IPCS 2002 with Permission.)
•
Homeostatic mechanisms should be identifi ed for the selected
ETE.
•
Variations of the population's homeostatic adaptation must be
considered.
•
There is a “zone of safe and adequate exposure for each defi ned
age and gender groups” for all EMs - a zone compatible with
good health. This is the acceptable range of oral intake (AROI).
•
All appropriate scientifi c disciplines must be involved in
developing an AROI.
•
Data on toxicity and defi ciency should receive equal critical
evaluation.
•
Bioavailability should be considered in assessing the effects of
defi ciency and toxicity.
•
Nutrient interactions should be considered when known.
•
Chemical species and the route and duration of exposure
should be fully described.
•
Biological end-points used to defi ne the lower (RDA) and
upper (toxic) boundaries of the AROI should ideally have
similar degrees of functional signifi cance. This is particularly
relevant where there is a potentially narrow AROI as a result
of one end-point being of negligible clinical signifi cance.
•
All appropriate data should be used to determine the dose-
response curve for establishing the boundaries of the AROI.
been presented by WHO (WHO/IPCS, 2002). This
scheme is reproduced with permission in Figure 3.
The scheme in Figure 3 should not be considered a
new paradigm for assessing human health risks from
exposure to EMs. In fact, the steps shown are essen-
tially the same as those shown for the risk assessment
of metals in general (see Chapter 14). One major dif-
ference is the need to apply each step to data related
to essentiality and toxicity for the EM. This requires
a multidisciplinary team of scientists, applying the
principles in Table 2, and using a weight of evidence
approach, applying sound scientifi c judgement at each
step. The entire scheme is an iterative process.
In step 6, risk characterization, data on exposure and
the AROI are integrated. This process takes into consid-
eration the variability in exposure and dose-response
for multiple subpopulations, evaluating the strengths
and weaknesses of the evaluations at each step (WHO/
IPCS, 1999). Transparency during each step is impor-
tant but particularly so during the risk characterization.
It is essential to ensure scientifi c conclusions are identi-
fi ed separately from policy judgments. Also, the use of
default values or methods during the risk assessment
must be clearly identifi ed and discussed (WHO/IPCS,
2002). Based on the wide-ranging expertise of groups
carrying out risk assessments of EMs, an important role
of risk characterization is the identifi cation of research
4 SUMMARY OF PRINCIPLES FOR
HUMAN RISK ASSESSMENT
OF EXPOSURES TO EMs
WHO (WHO/IPCS, 2002) developed a set of prin-
ciples for the use of the “homeostatic model” in the
assessment of human health risks from exposure to
essential trace nutrients. These are presented, with
permission, in Table 2. Many of these principles were
examined at a workshop in 1992 (Mertz, 1993; Mertz
et
al.
, 1994) and have been discussed briefl y elsewhere in
this chapter or in the references provided.
It is beyond the scope of this chapter to discuss in
detail the known physiological adaptation to chang-
ing levels of intake of EMs and the variables affecting
this adaptation. However, as noted by WHO (WHO,
1996; WHO/IPCS, 2002), this will play an important
role in the risk assessment of essential trace nutrients,
including EMs.
4.1 Application of Principles for
Determination of AROI
A proposed scheme for the application of the prin-
ciples in Table 2 for the determination of an AROI has
