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Cádmio na saúde humana

Historical perspectives on cadmium toxicology

Gunnar F. Nordberga,
Environmental Medicine, Department of Public Health and Clinical Medicine, Umeå
University, SE-90187 Umeå, Sweden


The first health effects of cadmium (Cd) were reported already in 1858. Respiratory and
gastrointestinal symptoms occurred among persons using Cd-containing polishing
agent. The first experimental toxicological studies are from 1919. Bone effects and
proteinuria in humans were reported in the 1940's. After World War II, a bone disease
with fractures and severe pain, the itai-itai disease, a form of Cd-induced renal
osteomalacia, was identified in Japan. Subsequently, the toxicokinetics and
toxicodynamics of Cd were described including its binding to the protein
metallothionein. International warnings of health risks from Cd-pollution were issued in
the 1970's. Reproductive and carcinogenic effects were studied at an early stage, but a
quantitative assessment of these effects in humans is still subject to considerable
uncertainty. The World Health Organization in its International Program on Chemical
Safety, WHO/IPCS (1992) (Cadmium. Environmental Health Criteria Document 134,
IPCS. WHO, Geneva, 1–280.) identified renal dysfunction as the critical effect and a
crude quantitative evaluation was presented. In the 1990's and 2000 several
epidemiological studies have reported adverse health effects, sometimes at low
environmental exposures to Cd, in population groups in Japan, China, Europe and USA
(reviewed in other contributions to the present volume). The early identification of an
important role of metallothionein in cadmium toxicology formed the basis for recent
studies using biomarkers of susceptibility to development of Cd-related renal
dysfunction such as gene expression of metallothionein in peripheral lymphocytes and
autoantibodies against metallothionein in blood plasma. Findings in these studies
indicate that very low exposure levels to cadmium may give rise to renal dysfunction
among sensitive subgroups of human populations such as persons with diabetes.

Keywords: Cadmium and human health; Cadmium toxicokinetics; Cadmium

toxicodynamics; Historical risk assessment of cadmium exposure; Mechanisms of
cadmium toxicity

Current status of cadmium as an environmental health problem

Lars Järupa, b, ,
and Agneta Åkessonb
Department of Epidemiology and Public Health, Imperial College London, UK
Institute of Environmental Medicine, Karolinska Institutet, Stockholm, Sweden


Cadmium is a toxic metal occurring in the environment naturally and as a pollutant

emanating from industrial and agricultural sources. Food is the main source of cadmium
intake in the non-smoking population. The bioavailability, retention and toxicity are
affected by several factors including nutritional status such as low iron status. Cadmium
is efficiently retained in the kidney (half-time 10–30 years) and the concentration is
proportional to that in urine (U-Cd). Cadmium is nephrotoxic, initially causing kidney
tubular damage. Cadmium can also cause bone damage, either via a direct effect on
bone tissue or indirectly as a result of renal dysfunction. After prolonged and/or high
exposure the tubular injury may progress to glomerular damage with decreased
glomerular filtration rate, and eventually to renal failure. Furthermore, recent data also
suggest increased cancer risks and increased mortality in environmentally exposed
populations. Dose–response assessment using a variety of early markers of kidney
damage has identified U-Cd points of departure for early kidney effects between 0.5 and
3 µg Cd/g creatinine, similar to the points of departure for effects on bone. It can be
anticipated that a considerable proportion of the non-smoking adult population has
urinary cadmium concentrations of 0.5 µg/g creatinine or higher in non-exposed areas.
For smokers this proportion is considerably higher. This implies no margin of safety
between the point of departure and the exposure levels in the general population.
Therefore, measures should be put in place to reduce exposure to a minimum, and the
tolerably daily intake should be set in accordance with recent findings.

Keywords: Cadmium exposure; Kidney effects; Bone effects; Cancer; Epidemiological

studies; Risk assessment

Monitoring of human populations for early markers of cadmium

toxicity: A review

Bruce A. Fowlera,
Division of Toxicology and Environmental Medicine, Agency for Toxic Substances
and Disease Registry, Atlanta, GA 30333, USA


Exposure of human populations to cadmium (Cd) from air, food and water may produce
effects in organs such as the kidneys, liver, lungs, cardiovascular, immune and
reproductive systems. Since Cd has been identified as a human carcinogen, biomarkers
for early detection of susceptibility to cancer are of an importance to public health. The
ability to document Cd exposure and uptake of this element through biological
monitoring is a first step towards understanding its health effects. Interpretation and
application of biological monitoring data for predicting human health outcomes require
correlation with biological measures of organ system responses to the documented
exposure. Essential to this understanding is the detection and linkage of early biological
responses toxic effects in target cell populations. Fortunately, advances in cell biology
have resulted in the development of pre-clinical biological markers (biomarkers) that
demonstrate measurable and characteristic molecular changes in organ systems
following chemical exposures that occur prior to the onset of overt clinical disease or
development of cancer. Technical advances have rendered a number of these
biomarkers practical for monitoring Cd-exposed human populations. Biomarkers will be
increasingly important in relation to monitoring effects from the exposure to new Cd-
based high technology materials. For example, cadmium-selenium (CdSe), nano-
materials made from combinations of these elements have greatly altered cellular uptake
characteristics due to particle size. These differences may greatly alter effects at the
target cell level and hence risks for organ toxicities from such exposures. The value of
validated biomarkers for early detection of systemic Cd-induced effects in humans
cannot be underestimated due to the rapid expansion of nano-material technologies.
This review will attempt to briefly summarize the applications, to date, of biomarker
endpoints for assessing target organ system effects in humans and experimental systems
from Cd exposure. Further, it will attempt to provide a prospective look at the possible
future of biomarkers. The emphasis will be on the detection of early toxic effects from
exposure to Cd in new products such as nano-materials and identification of populations
at special risk for Cd toxicity.

Keywords: Cadmium; Biomarkers; Kidney; Liver; Lung; Cardiovascular; Immune;

Reproductive organs; Cadmium Nanomaterials

Cadmium-induced testicular injury

Erica R. Siua, Dolores D. Mruka, Catarina S. Portob and C. Yan Chenga, ,

Center for Biomedical Research, Population Council, 1230 York Avenue, New York,
NY 10065, USA
Section of Experimental Endocrinology, Department of Pharmacology, Universidade
Federal de Sao Paulo, Escola Paulista de Medicina, Rua Tres de maio 100, INFAR, Vila
Clementino, Sao Paulo, SP04044-020, Brazil


Cadmium (Cd) is an environmental toxicant and an endocrine disruptor in humans and

rodents. Several organs (e.g., kidney, liver) are affected by Cd and recent studies have
illustrated that the testis is exceedingly sensitive to Cd toxicity. More important, Cd and
other toxicants, such as heavy metals (e.g., lead, mercury) and estrogenic-based
compounds (e.g., bisphenols) may account for the recent declining fertility in men
among developed countries by reducing sperm count and testis function. In this review,
we critically discuss recent data in the field that have demonstrated the Cd-induced
toxicity to the testis is probably the result of interactions of a complex network of
causes. This is likely to involve the disruption of the blood–testis barrier (BTB) via
specific signal transduction pathways and signaling molecules, such as p38 mitogen-
activated protein kinase (MAPK). We also summarize current studies on factors that
confer and/or regulate the testis sensitivity to Cd, such as Cd transporters and
metallothioneins, the impact of Cd on the testis as an endocrine disruptor and oxidative
stress inducer, and how it may disrupt the Zn2+ and/or Ca2+ mediated cellular events.
While much work is needed before a unified mechanistic pathway of Cd-induced
testicular toxicity emerges, recent studies have helped to identify some of the likely
mechanisms and/or events that take place during Cd-induced testis injury. Furthermore,
some of the recent studies have shed lights on potential therapeutic or preventive
approaches that can be developed in future studies by blocking or minimizing the
destructive effects of Cd to testicular function in men.

Keywords: Environmental toxicant; Cadmium; Testis; Spermatogenesis; Seminiferous

epithelial cycle; Sertoli cells; Germ cells; Blood–testis barrier; Cell adhesion; Infertility;

Cadmium, diabetes and chronic kidney disease

, a,
Joshua R. Edwards and Walter C. Prozialecka
Department of Pharmacology, Midwestern University, Downers Grove, IL 60515, USA


Recent epidemiological studies suggest a positive association between exposure to the

environmental pollutant cadmium (Cd) and the incidence and severity of diabetes. In
this review, we examine the literature suggesting a relationship between Cd exposure,
elevated blood glucose levels, and the development of diabetes. In addition we review
human and animal studies indicating that Cd potentiates or exacerbates diabetic
nephropathy. We also review the various possible cellular mechanisms by which Cd
may alter blood glucose levels. In addition, we present some novel findings from our
own laboratories showing that Cd elevates fasting blood glucose levels in an animal
model of subchronic Cd exposure before overt signs of renal dysfunction are evident.
These studies also show that Cd reduces insulin levels and has direct cytotoxic effects
on the pancreas. Together, these findings indicate that Cd may be a factor in the
development of some types of diabetes and they raise the possibility that Cd and
diabetes-related hyperglycemia may act synergistically to damage the kidney.

Keywords: Cadmium; Diabetes; Fasting blood glucose; Insulin; A1