CADMIUM
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Agency for Toxic Substances and Disease Registry

U.S. Public Health Service
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                                                        ATSDR/TP-88/08
           TOXICOLOGICAL PROFILE FOR
                     CADMIUM
             Date Published — March 1989
                     Prepared by:

                   Life Systems. lac.
             under Contract No. 68-02-4228

                         for

Agency for Toxic Substances and Disease Registry (ATSDR)
               U.S. Public Health Service

                 in collaboration with

      U.S. Environmental Protection Agency (EPA)
       Technical editing/document preparation by:

            Oak Ridge National Laboratory
                       under
     DOE Interagency Agreement No. 1857-B026-A1

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                         DISCLAIMER

Mention of company name or product does not constitute endorsement by
the Agency for Toxic Substances and Disease Registry.

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                                FOREWORD

     The Superfund Amendments and Reauthorization Act of 1986 (Public
Lav 99-499) extended and amended the Comprehensive Environmental
Response, Compensation, and Liability Act of 1980 (CERCLA or Superfund).
This public law (also known as SARA) directed the Agency for Toxic
Substances and Disease Registry (ATSDR) to prepare toxicological
profiles for hazardous substances which are most commonly found at
facilities on the CERCLA National Priorities List and which pose the
most significant potential threat to human health, as determined by
ATSDR and the Environmental Protection Agency (EPA). The list of the 100
most significant hazardous substances was published in the Federal
Register on April 17, 1987.
     Section 110 (3) of SARA directs the Administrator of ATSDR to
prepare a toxicological profile for each substance on the list. Each
profile must include the following content:
     "(A)  An examination, summary, and interpretation of available
     toxicological information and epidemiologic evaluations on a
     hazardous substance in order to ascertain the levels of significant
     human exposure for the substance and the associated acute,
     subacute, and chronic health effects.
     (B)  A determination of whether adequate information on the health
     effects of each substance is available or in the process of
     development to determine levels of exposure which present a
     significant risk to human health of acute, subacute, and chronic
     health effects.
     (C)  Where appropriate, an identification of toxicological testing
     needed to identify the types or levels of exposure that may present
     significant risk of adverse health effects in humans."
     This toxicological profile is prepared in accordance with
guidelines developed by ATSDR and EPA. The guidelines were published in
the Federal Register on April 17, 1987. Each profile will be revised and
republished as necessary, but no less often than every three years, as
required by SARA.
     The ATSDR toxicological profile is intended to characterize
succinctly the toxicological and health effects information for the
hazardous substance being described. Each profile identifies and reviews
the key literature that describes a hazardous substance's toxicological
properties. Other literature is presented but described in less detail
than the key studies. The profile is not intended to be an exhaustive
document; however, more comprehensive sources of specialty information
are referenced.
                                                                      iii

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Foreword
     Each toxicological profile begins with a public health statement,
which describes in nontechnical language a substance's relevant
toxicological properties. Following the statement is material that
presents levels of significant human exposure and, where known,
significant health effects. The adequacy of information to determine a
substance's health effects is described in a health effects summary.
Research gaps in toxicologic and health effects information are
described in the profile. Research gaps that are of significance to
protection of public health will be identified by ATSDR, the National
Toxicology Program of the Public Health Service, and EPA. The focus of
the profiles is on health and toxicological information; therefore, we
have included this information in the front of the document.
     The principal audiences for the toxicological profiles are health
professionals at the federal, state, and local levels, interested
private sector organizations and groups, and members of the public. Ve
plan to revise these documents in response to public comments and as
additional data become available; therefore, we encourage comment that
will make the toxicological profile series of the greatest use.
     This profile reflects our assessment of all relevant toxicological
testing and information that has been peer reviewed. It has been
reviewed by scientists from ATSDR, EPA, the Centers for Disease Control,
and the National Toxicology Program. It has also been reviewed by a
panel of nongovernment peer reviewers and was made available for public
review. Final responsibility for the contents and views expressed in
this toxicological profile resides with ATSDR.
                                    James 0. Mason, M.D., Dr. P.H.
                                    Assistant Surgeon General
                                    Administrator, ATSDR
 iv

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                                CONTENTS

FOREWORD 	  HI
LIST OF FIGURES 	   ix
LIST OF TABLES 	   xi
 1.   PUBLIC HEALTH STATEMENT 	    1
     1.1  WHAT IS CADMIUM? 	    1
     1.2  HOW MIGHT I BE EXPOSED TO CADMIUM? 	    1
     1.3  HOW DOES CADMIUM GET INTO MY BODY? 	    1
     1.4  HOW CAN CADMIUM AFFECT MY HEALTH? 	    2
     1.5  IS THERE A MEDICAL TEST TO DETERMINE IF I HAVE
          BEEN EXPOSED TO CADMIUM? 	    2
     1.6  WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL
          HEALTH EFFECTS? 	    3
     1.7  WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT
          MADE TO PROTECT HUMAN HEALTH? 	    3
 2.   HEALTH EFFECTS SUMMARY 	    7
     2.1  INTRODUCTION 	    7
     2.2  LEVELS OF SIGNIFICANT EXPOSURE 	    8
          2.2.1  Key Studies 	    8
                 2.2.1.1  Inhalation 	    8
                 2.2.1.2  Oral 	   13
                 2.2.1.3  Dermal	   18
          2.2.2  Biological Monitoring as a Measurement of
                 Exposure and Effects 	   18
                 2.2.2.1  Exposure 	   18
                 2.2.2.2  Biological effects 	   20
          2.2.3  Environmental Levels as Indicators of
                 Exposure and Effects 	   21
                 2.2.3.1  Levels found In the environment 	   21
                 2.2.3.2  Human exposure potential 	   22
     2.3  ADEQUACY OF DATABASE 	   22
          2.3.1  Introduction 	   22
          2.3.2  Health Effect End Points 	   23
                 2.3.2.1  Introduction and graphic summary 	   23
                 2.3.2.2  Description of highlights of graphs 	   26
                 2.3.2.3  Summary of relevant ongoing research ....   26
          2.3.3  Other Information Needed for Human
                 Health Assessment 	   26
                 2.3.3.1  Pharmacoklnetlcs and mechanisms
                          of action 	   26
                 2.3.3.2  Monitoring of human biological samples ..   29
                 2.3.3.3  Environmental considerations  	   29

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Contents

 3.   CHEMICAL AND PHYSICAL INFORMATION 	   31
     3.1  CHEMICAL IDENTITY 	   31
     3.2  PHYSICAL AND CHEMICAL PROPERTIES 	   31

 4.   TOXICOLOGICAL DATA 	   35
     4.1  OVERVIEW 	   35
     4.2  TOXICOKINETICS 	   36
          4.2.1  Overview 	   36
          4.2.2  Absorption 	   36
                 4.2.2.1  Inhalation 	   36
                 4.2.2.2  Oral 	   37
                 4.2.2.3  Dermal	   38
          4.2.3  Distribution 	   38
          4.2.4  Metabolism 	   41
          4.2.5  Excretion 	   42
     4.3  TOXICITY 	   42
          4.3.1  Lethality 	   42
          4.3.2  Systemic/Target Organ Toxicity 	   42
                 4.3.2.1  Overview 	   42
                 4.3.2.2  Renal effects 	   43
                 4.3.2.3  Hepatic effects 	   45
                 4.3.2.4  Cardiovascular effects 	   46
                 4.3.2.5  Pulmonary effects 	   47
                 4.3.2.6  Gastrointestinal effects 	   47
                 4.3.2.7  Skeletal effects 	   47
                 4.3.2.8  Effects on the immune system	   48
                 4.3.2.9  Effects on testes, ovaries,
                          and placenta 	   48
                 4.3.2.10 Other systemic effects 	   49
          4.3.3  Developmental Toxicity 	   50
          4.3.4  Reproductive Toxicity 	   51
          4.3.5  Genotoxicity 	   52
                 4.3.5.1  Gene mutation studies 	   52
                 4.3.5.2  Chromosomal aberration studies 	   52
          4.3.6  Careinogenieity 	   52
                 4.3.6.1  Inhalation	   52
                 4.3.6.2  Oral  	   55
                 4.3.6.3  Dermal	   56
     4.4  INTERACTIONS WITH OTHER CHEMICALS 	   56

  5.  MANUFACTURE,  IMPORT, USE, AND DISPOSAL	   57
     5.1  OVERVIEW 	   57
     5.2  PRODUCTION 	   57
     5.3  IMPORT 	   57
     5.4  USE 	   57
     5.5  DISPOSAL 	   57

  6.  ENVIRONMENTAL FATE  	   59
     6.1  OVERVIEW 	   59
     6.2  RELEASES TO  THE ENVIRONMENT 	   59
          6.2.1  Anthropogenic  	  59
          6.2.2  Natural  	  60
     6.3  ENVIRONMENTAL FATE  	  60
          6.3.1  Atmosphere  	  6°
          6.3.2  Surface Water  	  60
 vi

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                                                                Concents

          6.3.3  Groundwater 	   61
          6.3.4  Soil 	   61
          6.3.5  Biota 	   61

 7.   POTENTIAL FOR HUMAN EXPOSURE 	   63
     7.1  OVERVIEW 	   63
     7.2  LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT 	   63
          7.2.1  Water 	   63
          7.2.2  Air 	   64
          7.2.3  Soil 	   64
          7.2.4  Biota and Food 	   65
          7.2.5  Resulting Background Exposure Levels 	   65
     7.3  OCCUPATIONAL EXPOSURES 	   65
     7.4  POPULATIONS AT HIGH RISK 	   66
          7.4.1  Above-Average Exposure 	   66
          7.4.2  Above-Average Sensitivity 	   66

 8.   ANALYTICAL METHODS 	   67
     8.1  ENVIRONMENTAL MEDIA 	   67
          8.1.1  Air 	   67
          8.1.2  Water 	   67
          8.1.3  Soil 	   67
          8.1.4  Food 	   69
     8.2  BIOLOGICAL SAMPLES 	   69
          8.2.1  Fluids and Exudates 	   69
          8.2.2  Tissues 	   69

 9.   REGULATORY AND ADVISORY STATUS 	   71
     9.1  INTERNATIONAL 	   71
     9.2  NATIONAL 	   71
          9.2.1  Regulations 	   71
                 9.2.1.1  Air 	   71
                 9.2.1.2  Water	   71
                 9.2.1.3  Reportable quantities 	   74
                 9.2.1.4  Waste disposal 	   74
                 9.2.1.5  Pesticide	   75
          9.2.2  Advisory Guidance 	   75
                 9.2.2.1  Air 	   75
                 9.2.2.2  Water	   75
          9.2.3  Data Analysis  	   76
                 9.2.3.1  Reference dose 	   76
                 9.2.3.2  Carcinogenic potency 	   76
     9.3  STATE  	   77
          9.3.1  Regulations 	   77
          9.3.2  Advisory Guidance 	   77

10.   REFERENCES  	   79

11.   GLOSSARY  	  103
APPENDIX:  PEER REVIEW 	  107
                                                                     vll

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                            LIST OF FIGURES
1.1  Health effects from breathing cadmium 	    4
1.2  Health effects from ingesting cadmium 	   5
2.1  Effects of cadmium-- inhalation exposure 	   9
2.2  Levels of significant exposure for cadmium--inhalation  	  10
2.3  Effects of cadmium--oral exposure 	  14
2.4  Levels of significant exposure for cadmium--oral  	  IS
2.5  Availability of information on health effects  of  cadmium
     (human data) 	  24
2.6  Availability of information on health effects  of  cadmium
     (animal data) 	  25
                                                                      ix

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                             LIST OF TABLES
2.1  Summary of ongoing research projects related to cadmium 	    27
3.1  Chemical identity of cadmium and selected cadmium compounds  ..   32
3.2  Physical and chemical properties of cadmium
     and selected cadmium compounds 	   33
4.1  Mean cadmium levels in human cadaver tissues in Japan 	   39
4.2  Cadmium concentration in tissues of rats exposed
     through drinking water 	   40
8.1  Analytical methods for cadmium in environmental samples 	   68
8.2  Analytical methods for cadmium in biological samples 	   70
9.1  Regulations and guidelines applicable to cadmium 	   72
9.2  Summary of lung cancer risk estimates for
     inhalation exposure to cadmium 	   78
                                                                      xi

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                      1.  PUBLIC HEALTH STATEMENT

l.L  WHAT IS CADMIUM?
     Cadmium is a naturally occurring element in the earth's crust.  Pure
cadmium is a soft silver-white metal, but this form is not common in the
environment. Rather, cadmium is most often encountered in combination
with other elements such as oxygen (cadmium oxide), chlorine (cadmium
chloride), or sulfur (cadmium sulfide).  These compounds are all stable
solids that do not evaporate, although cadmium oxide is often found as
part of small particles present in air.
     Most cadmium used in this country is obtained as a by-product from
the smelting of zinc, lead, or copper ores. Cadmium has a number of
industrial applications, but it is used mostly in metal plating,
pigments, batteries, and plastics.

1.2  HOV MIGHT I BE EXPOSED TO CADMIUMT
     Small quantities of cadmium occur naturally in air, water, soil,
and food. For most people, food is the primary source of cadmium
exposure, since food materials tend  to take up and retain cadmium. For
example, plants take up cadmium from soil, fish take up cadmium from
water, and so on.
     The application of phosphate fertilizers or sewage sludge may
increase cadmium levels in soil, which, in turn, can cause  increased
cadmium levels in crops. Cadmium is  not often encountered at levels of
concern in water, although it can leach into water from pipes and solder
or may enter water from chemical waste disposal sites.
     The largest source of cadmium release to the  general environment is
the burning of fossil fuels  (such as coal or oil)  or the incineration of
municipal waste materials. Cadmium may also escape into the air from
zinc, lead, or copper smelters. Working in or living close  to a major
source of airborne emissions such as these may result  in higher-than-
average exposure.
     Socking  is another important source of cadmium. Like most  plants,
tobacco contains cadmium, some of which is inhaled in  cigarette smoke.
Most people who smoke have about  twice as much cadmium in their bodies
as do nonsmokers.

1.3  HOV DOES CADMIUM GET  INTO MY BODYf
     Cadmium  can enter  the blood by  absorption from  the stomach or
intestines  after ingest ion of  food or water,  or by absorption  from  the
lungs after  inhalation. Very little  cadmium  enters the body through the
skin. Usually only  about  1  to  5%  of  what  is  taken in by mouth  is
absorbed  into the blood, while  about 30  to 50% of that which is inhaled

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2   Section 1

is taken up into the blood. However, once cadmium enters the body, it is
very strongly retained; therefore, even low doses may build up
significant cadmium levels in the body if exposure continues for a long
time.

1.4  HOW CAN CADMIUM AFFECT MY HEALTH?
     Cadmium is not known to have any beneficial effects,  but can cause
a number of adverse health effects. Ingestion of high doses causes
severe irritation to the stomach, leading to vomiting and diarrhea;
inhalation of high doses leads to severe irritation of the lungs. Such
high exposures, however, are extremely rare today. Of greater concern
are the effects which may occur following long-term, low-level exposure.
Examples of effects resulting from various levels and durations of
exposure are as follows:
   • Kidney damage has been observed in people who are exposed to excess
     cadmium either through air or through the diet. This kidney disease
     is usually not life threatening, but it can lead to the formation
     of kidney stones and effects on the skeleton that are equally
     painful and debilitating.
   • Lung damage, such as emphysema, has been observed in workers in
     factories where levels of cadmium concentration in air are high.

   • Lung cancer has been shown to occur in animals exposed for  long
     periods to cadmium in air. Studies in humans also suggest that
     long-term inhalation of cadmium can result in  increased risk of
     lung cancer. Oral exposure to cadmium is not believed to cause
     cancer.
   • High blood pressure has been observed in animals exposed to
     cadmium. Whether or not cadmium exposure plays an important  role  in
     human hypertension is not yet known and requires further research.
     Other tissues reported to be injured by cadmium exposure in animals
or humans include the  liver, the  testes, the immune system, the  nervous
system, and  the blood. Reproductive and developmental effects have been
observed in  animals treated with  cadmium, but these have not been
reported in  humans.

1.5  IS THERE A MEDICAL TEST TO DETERMINE IF I  HAVE BEEN
     EXPOSED TO CADMIUM?
     There are several ways  that  an individual  may  be tested  for
excessive cadmium exposure. One  involves measuring  the  amount of cadmium
present  in blood, urine,  or hair. The  amount in blood is  a good
 indicator of recent exposures, whereas the  amount in urine is a
 reflection of how much total  cadmium is  present in  the  body.  The amount
 of cadmium  in hair  is  not usually considered to be  reliable,  since
 cadmium  can  bind  to  the  outside  of hair and give faulty results. Another
 approach is  to measure cadmium concentrations  in the  liver or kidney,
 using  a  process called neutron activation analysis. While this  method
 gives  a  very useful  indication of the amount of cadmium in the  body,  it
 is usually  too costly and inconvenient for routine  use.

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                                             Public Health Statement   3

1.6  WHAT LEVELS OF EXPOSURE HAVE RESULTED IN HARMFUL HEALTH EFFECTST

     The amount of cadmium needed to cause an adverse effect In an
exposed person depends on the chemical and physical form of the element.
In general, cadnTiuorcompounds that dissolve easily in water (e.g.,
cadmium chloride), or those that can be dissolved in the body (e.g.,
cadmium oxide), tend to be more toxic than compounds that are very hard
to dissolve (e.g., cadmium sulfide).

     The graphs on the following pages (Figs. 1.1 and 1.2) show the
relationship between exposure to cadmium  (either soluble cadmium
compounds or cadmium oxide) and known health effects. In the first set
of graphs labeled "Health effects from breathing cadmium," exposure is
expressed as milligrams of cadmium per cubic meter of air (mg/m3). In
all graphs, effects in animals are shown  on the left side, effects in
humans on the right.

     In the second set of graphs, the same relationship is represented
for the known "Health effects from ingesting cadmium." Exposures are
measured in milligrams of cadmium per kilogram of body weight per day
(mg/kg/day) .

     By the inhalation route (Fig. 1.1),  airborne concentrations of
1 mg/m3 are associated with acute irritation to the lung, and long-tern
exposure to levels of 0.1 mg/m3 may increase the risk of lung disease
such as emphysema. These same levels are  also associated with
development of kidney injury similar to that observed following oral
exposure. Long-term exposure to a level of 0.02 mg/m3 is thought to pose
relatively little risk of injury to lung  or kidney.
     Based on available data from studies of humans, it has been
estimated that lifelong inhalation of air containing 1 Mg/m3 (0.001
mg/m3) of cadmium is associated with a risk of lung cancer of about 2 in
1,000.

     Figure 1.2 summarizes the effects observed in humans and animals
exposed to cadmium orally. For soluble cadmium compounds, an oral dose
of about 0.05 mg/kg (3.5 mg in an adult)  is considered to be the minimum
which causes irritation to the stomach. Long-term intake of up to about
0.005 mg/kg/day (0.35 mg/day in an adult) is believed to have relatively
little risk of causing injury to the kidney or other,, tissues. As noted
above, ingestion of cadmium is not believed to pose a cancer risk.
     Levels of cadmium exposure through food, water, and air that are
typical for most people are not of major  health concern. For example,
the intake of cadmium from the diet is usually about 0.0004 mg/kg/day,
roughly ten times lower than the typical  amount needed to cause kidney
damage by this route.

1.7  WHAT RECOMMENDATIONS HAS THE FEDERAL GOVERNMENT MADE TO PROTECT
     HUMAN HEALTH?

     The government has taken a number of step* to protect humans from
excessive cadmium exposure. The Environmental Protection Agency (EPA)
has established limits on the quantity of cadmium that can be discharged
into water or disposed of as solid wastes from factories that

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   4   Section 1
       SHORT-TERM EXPOSURE
   (LESS THAN OR EQUAL TO 14 DAYS)
EFFECTS
   IN
ANIMALS
CONG IN
  AIR
 (mg/m3)

  1000
EFFECTS
   IN
HUMANS
LETHALITY  -
(10 MINUTES)
                       	LETHALITY
                          (10 MINUTES)
   100
                   10
EFFECTS ON	•<
FETUS
      u
      I   <8
                          LETHALITY
                            HOURS)
                   10
                                     LONG-TERM EXPOSURE
                                    (GREATER THAN 14 DAYS)
EFFECTS
   IN
ANIMALS
CONC IN
  AIR
 (mg/m3)


  1000
                                           100
                                          LETHALITY —<
                       — LUNG IRRITATION
                                          LUNG
                                          DISEASE
                   0.1
                                                           10
                                                           1.0
                                                       v   0.1
EFFECTS
   IN
HUMANS
                                                                    CHRONIC LUNG
                                                                    DISEASE.
                                                                    KIDNEY
                                                                    DISEASE
                  0.01
                 0.001
                                                          001
                                          0001
                       Fig. 1.1. HcaHk effects tnm breatfclig

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                                                    Public Health Seacement
        SHORT-TERM EXPOSURE
   (LESS THAN OR EQUAL TO 14 DAYS)
 EFFECTS
    IN
 ANIMALS
LETHALITY
DECREASED
WEIGHT OF -
OFFSPRING
  DOSE
(mg/kg/day)

  1000
EFFECTS
   IN
HUMANS
                  100
                        — LETHALITY
    10
                  1 0
                  o.i   y —
            STOMACH
            IRRITATION
                 0.01
                                      LONG-TERM EXPOSURE
                                     (GREATER THAN 14 DAYS)
EFFECTS EFFECTS
IN DOSE IN
ANIMALS (mg/kg/day) HUMANS
100
1C
1
KIDNEY (
DAMAGE
BREEDING
FAILURE
ALTERED
BEHAVIOR 	
OF NEWBORN
INCREASED
BLOOD 	 <
PRESSURE
r
1

0
OC
0
0
0

0

1
1 LOWEST DOSE
1 I THOUGHT TO
PRODUCE
KIDNEY
DAMAGE
                0.001
                                                         0001
                      Fig. 1.2.  Health effects from ingesting cadmium.

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6   Section 1

manufacture or employ cadmium. It is considering regulations that would
limit the amount of cadmium that could be emitted into outside air. EPA
has also established an interim Maximum Contaminant Level (MCL) of
0.01 mg/L (10 jig/L) for cadmium in drinking water.  It has proposed a
Maximum Contaminant Level Goal (MCLG) of 0.005 mg/L (5 Mg/L).
     The Occupational Safety and Health Administration (OSHA) has
established average and maximum (ceiling) permissible exposure limits to
cadmium dust and fumes in workplace air. In view of the potential
carcinogenic risk from the inhalation of cadmium,  the National Institute
for Occupational Safety and Health (NIOSH) recommends chat controls be
used to reduce worker exposure to the fullest extent feasible.  The Food
and Drug Administration (FDA) limits the amount of cadmium that can be
used in ceramic plates and cups.

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                        2.   HEALTH EFFECTS  SUMMARY

 2.1   INTRODUCTION

      This  section  summarizes  and graphs data on  the health effects
 concerning exposure  to  cadmium.  The  purpose of this section  is to
 present levels of  significant exposure for cadmium based on  key
 toxicological studies,  epidemiological investigations, and environmental
 exposure data. The information presented in this section is  critically
 evaluated  and discussed in  Sect.  4,  Toxicological Data, and  Sect. 7,
 Potential  for Human  Exposure.

      This  Health Effects Summary section comprises two major parts.
 Levels of  Significant Exposure (Sect. 2.2) presents brief narratives and
 graphics for key studies in a manner that  provides public health
 officials,  physicians,  and  other interested individuals and  groups with
 (1) an overall perspective  of the toxicology of cadmium and  (2) a
 summarized depiction of significant  exposure levels associated with
 various adverse health  effects.  This section also includes information
 on the levels of cadmium that have been monitored in human fluids and
 tissues and information about levels of cadmium found in environmental
 media and  their association with human exposures.

     The significance of the  exposure levels shown on the graphs may
 differ depending on  the user's perspective. For example, physicians
 concerned  with the interpretation of overt clinical findings in exposed
 persons or with the  identification of persons with the potential to
 develop such disease may be interested in  levels of exposure associated
with frank effects (Frank Effect Level, FEL). Public health  officials
 and project managers concerned with  response actions at Superfund sites
may wane information on levels of exposure associated with more subtle
effects in humans  or animals  (Lowest-Observed-Adverse-Effect Level,
LOAEL) or  exposure levels below  which no adverse effects (No-Observed-
Adverse-Effect Level, NOAEL)  have been observed. Estimates of levels
posing minimal risk  to  humans  (Minimal Risk Levels) are of interest to
health professionals and citizens alike.

     Adequacy of Database (Sect.  2.3) highlights the availability of key
 studies on exposure  to  cadmium in the scientific literature  and displays
 these data in three-dimensional  graphs consistent with the format in
Sect. 2.2.  The purpose  of this section is  to suggest where there might
be insufficient information to establish levels of significant human
exposure.   These areas will  be  considered by the Agency for Toxic
Substances  and Disease  Registry  (ATSDR), EPA, and the National
Toxicology Program (NTP) of the  U.S.  Public Health Service in order to
develop a  research agenda for cadmium.

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8   Section 2

2.2  LEVELS OF SIGNIFICANT EXPOSURE

     To help public health professionals address the needs of persons
living or working near hazardous waste sites, the toxicology data
summarized in this section are organized first by route then by
exposure--inhalation, ingestion, and dermal--and then by toxicological
end points that are categorized into six general areas--lethality,
systemic/target organ toxlcity, developmental toxicity, reproductive
toxicity, genetic toxicity, and carcinogenicity. The data are discussed
in terms of three exposure periods--acute, intermediate,  and chronic.
     Two kinds of graphs are used to depict the data.  The first type is
a "thermometer" graph. It provides a graphical summary of the human and
animal toxicological end points (and levels of exposure)  for each
exposure route for which data are available. The ordering of effects
does not reflect the exposure duration or species of animal tested. The
second kind of graph shows Levels of Significant Exposure (LSE) for each
route and exposure duration. The points on the graph showing NOAELs and
LOAELs reflect the actual doses (levels of exposure) used in the key
studies. In all cases, exposure to cadmium compounds is expressed in
terms of the amount of cadmium, not of the compound. Where appropriate,
adjustments for exposure duration or intermittent exposure protocol were
made.

     Adjustments reflecting the uncertainty of extrapolating animal data
to man, intraspecies variations and differences between experimental vs
actual human exposure conditions were considered when estimates of
levels posing minimal risk to human health were made for noncancer end
points. These minimal risk levels were derived for the most sensitive
noncancer end point for each exposure duration by applying uncertainty
factors. These levels are shown on the graphs as a broken line starting
from the actual dose (level of exposure) and ending with a concave-
curved line at its terminus. Although methods have been established to
derive these minimal risk levels (Barnes et al. 1987), shortcomings
exist in the techniques that reduce the confidence in the projected
estimates. Also shown on the graphs under the cancer end point are low
level risks (10'4 to 10*7) reported by EPA. In addition,  the actual dose
(level of exposure) associated with the tumor incidence is plotted.

2.2.1  Key Studies

     The toxicity of cadmium depends on the chemical and physical forms
of the element. In general, soluble compounds (e.g., CdCl2) are better
absorbed and hence more toxic than highly insoluble compounds  (e.g.,
CdS), both by the inhalation and the oral routes (Rusch et al. 1986,
ILZRO 1977). Studies described here are focused mainly on cadmium oxide
or cadmium chloride, and the results cannot be applied equally to all
other cadmium compounds.

2.2.1.1  Inhalation
     The toxic effects of inhalation exposure to fumes, dusts, and
aerosols of cadmium compounds have been investigated in numerous studies
in animals and humans. Figures 2.1 and 2.2 summarize some of  these
studies which provide useful information on NOAELs and LOAELs  following
short-term and long-term Inhalation exposure to cadmium. Data  from

-------
                                                                           Health  Effects  Summery    9
  ANIMALS
   (rng/m j
  1000,-
  100
  10
  01
 001
0001
         • OOG LOW 10 MINUTES

         • RABBIT LDK 10 MINUTES
        • RAT MOUSE LD, 10 MINUTES
•  RABBIT EMPHYSEMA 8 MONTHS

•  RAT LETHALITY *i DAYS




•  RAT DECREASED BIRTH WEIGHT DAYS 1-22 OF GESTATION

•  RAT LUNGFIBROSIS 12 WEEKS
        o  RAT FERTILITY «-e MONTHS
        •  RAT ALTERED NEUROBEHAVCBAL DEVELOPMENT S MONTHS PLUS GESTATION
                                                                            HUMANS
                                                                             (mgnn1)

                                                                           1000 r
                                                                                    100
                                                                                    10
                                                                                    0 1
                                                                                  001
                                                                                 0001 <-
                                                                                       -  A
                                                                                  A  LETHALITY 10 MINUTES
                                                                                          A  LETHALITY 8H
                                                                                             MARKED LUNG INJURY
                                                                                             8M
                                                                                            ESTIMATED NOAEL
                                                                                            (RESPIRATORY INITIATION)
                                                                                            8H
                                                                                          A PPOTEINURIA to "EARS
                                                                                    ESTIMATED NOAEL
                                                                                    (RENAL) 20 YEARS*
                 • LOAEL IN ANIMALS
                 O NOAEL IN ANIMALS
                                                A LOAEL FOR HUMANS
                                                A NOAEL FOR HUMANS
        'Mv to tt» twt tar •
     flncdon of
                              of 9» «xp«ct»d fraojuncy or r«n«l if	in an mpoaad population a» a
                           Fig. 2.1.  Effects of cadmium—inhalation exposure.

-------
 10     Section  2
                      ACUTE
                    (SI 4 DAYS)
                     DEVELOP-  TARGET
           LETHALITY   MENTAL   ORGAN
                                    INTERMEDIATE
                                    (1S-3W DAYS)
                                     TARGET    REPRO-
                            LETHALITY ORGAN    OUCTION
                                            CHRONIC
                                           (2365 DAYS)
                                      TARGET
                                      ORGAN
                                                 CANCER
     1000
      100
       10
      1 0
      0 1
     001
     0001
    00001
   0 00001
  0 000001
 00000001
0 00000001
            • d
            • n
                  (10 MINUTES)
                A (8 HOURS)
                      (DECREASED
                      PUP WEIGHT)
                   (LUNG
                   MJURY)
                                *
                                 I
                                 I
                                       • h(EMPHYSEMA)
                                       • r(FIBHOSIS)
                                                                        A (LUNG
                                                                           CANCER)
                                                             (PROTEINURIA)"
                                                 OHFERTILITY)A           • rfl.UNG
                                                                           CANCER)
                                                                           I

                                                                           I
                                                                                   10-« -I
                                                                                   ID-' -
                                                                           ESTIMATED
                                                                           UPPER-BOUND
                                                                           HUMAN
                                                                           CANCER
                                                                           RISK LEVELS
                                                                    10-' J

 r  RAT      A LOAEL FOR HUMANS   •  LOAEL FOR ANIMALS   |   MINIMAL RISK LEVEL
d  DOS      A NOAEL FOR HUMANS   O  NOAEL FOR ANIMALS   i   FOR EFFECTS OTHER
m  MOUSE                                              >ix THAN CANCER
n  RABBIT
              to 9m twt for •
      tuncttono*
of ttw wpMttd ffVQuoncy ol ml
                                                      ki M wpOMd popunon M
                  Fig. 2.2.  Leveb of significant exposure for cadmium—inhalation.

-------
                                              Health  Effects  Summary   11

 studies  in humans  should be interpreted carefully, since  inhalation
 exposure to  dusts  and aerosols  may be  accompanied by significant oral
 exposure as  well.

     Lethality.  Inhalation of  cadmium oxide  (CdO) fumes  is  acutely
 toxic to the respiratory epithelium, although the appearance of symptoms
 is usually delayed several  hours.  Acute lethality is typically the
 result of marked pulmonary  edema (CEC  1978).

     In  animals, estimates  of the  LD5Q for cadmium oxide  following 10-
 to 30-min exposures  range from  500 to  4,000 (mg/m3)-min (Barrett et al.
 1947). Acute inhalation  lethality  in humans is relatively rare, and
 quantitative estimates of exposure are limited. Based on  measurements of
 the amount of cadmium found in  the lungs  in postmortem examinations
 following acute exposures to cadmium fumes, Barrett  et al. (1947)
 calculated the lethal inhalation exposure in  humans  to be about 2,500
 (mg/m3)-min.  A similar value was calculated by Beton et al.  (1966).
 This corresponds to  a concentration of about  250  mg/m3 for a 10-min
 exposure,  or about 5 mg/m3  for  an  8-h  exposure (Friberg et al. 1974,
 Elinder  1986b).

     Systemic toxicity.   As  noted  above,  the  principal tissue acutely
 affected by  inhalation exposure is the lung.  Exposure to  high levels
 results  in severe  bronchial  and pulmonary irritation, and Friberg et al.
 (1974) reported that exposure to 1 mg/m3  for  8 h  is  "immediately
 dangerous" to humans.  Bernard and  Lauwerys (1986) reported acute
 exposure  to  0.2 to 0.5 mg/m3 may cause mild and reversible symptoms
 similar  to metal fume fever, and the World Health Organization (WHO
 1980) identified 0.5 mg/m3  as the  threshold for respiratory  effects
 following an 8-h exposure.

     Following chronic low-level inhalation exposure, the tissues most
 often observed to  be affected are  the  kidney  and  lung. The respiratory
 effects generally  include bronchiolitis, alveolitis,  and  impaired
 respiratory  function,  and emphysema may develop in some cases. When
 renal effects occur,  they are characterized by the same sort of
microglobinuria as observed following  oral exposure. The  relative
 severity of  the effects  on  these tissues appears  to  depend primarily on
 the intensity of the exposure;  low levels are most likely to produce
 renal injury without marked lung injury, whereas  higher levels may cause
 lung injury before renal effects develop  (Elinder 1986b).

     Bonne11  (1955)  observed proteinuria  in 16% of a group of workers
exposed for  5 years  or more  to  cadmium oxide  in air  at concentrations
estimated  to range from  1 to 270 pg/m3 (King  1955),  and workers with
over 10 years of employment  were observed to  have increased  incidence of
emphysema. Bonne 11 (1955) emphasized that the emphysema may  have been
due to much higher concentrations  experienced by  the workers before the
exposure data were collected. Materne  et al.  (1975)  reported that kidney
 lesions occurred in  the  majority of workers exposed  to 20 pg/m3 for 27
years.  Kjellstrom  et al.  (1977a) reported that about 19%  of  workers with
6 to 12 years of exposure to cadmium dust at  a concentration of around
0.050 mg/m3 had tubular  proteinuria. More recently,  Kjellstrom (1986a)
estimated that chronic workplace exposure to  0.050 mg/m3  could lead to
proteinuria  in about 10% of  a population exposed  for 10 years, and that

-------
12   Section 2

0.016 mg/m3 would lead Co proteinuria in about 1% of the population.
Taken together, these data reveal a time- and dose-dependency for
cadmium-induced renal injury, with a value of about 0.5 (mg/m3)-years
being associated with proteinuria in some fraction of the exposed
workers. Based on a review of a number of epidemiological studies
(mostly in occupationally exposed groups), WHO (1980) concluded that  the
8-h time-weighted average concentration over a 20-year period should  not
exceed 0.02 mg/m3 (0.4 mg/m3 years). For continuous exposure (24 h/day),
the corresponding value is 0.007 mg/m3 (7 pg/a3).

     In animals, inhalation exposure also results in lung injury similar
to that seen in humans. Kutzman et al. (1986) exposed rats to aerosols
of CdCl2 from 0.3 to 2.0 mg/m3 cadmium, 6 h/day,  5 day/week for 12
weeks. Most of the animals exposed to 2 mg/m3 died within 45 days. A
dose-dependent development of fibretic lesions was observed at exposure
levels of 0.3 to 1.0 mg/m3. Evidence of emphysema was not detected in
this study, but Friberg (1950) reported emphysema in rabbits exposed  to
5 mg/m3 (3 h/day, 20 days/month) for 8 months.
     Developmental toxicIty.  The developmental effects of inhalation
exposure to cadmium have not been thoroughly studied, especially in
humans. Cvetkova (1970), as cited in Friberg et al. (1974), reported
that pregnant women exposed to high concentrations of cadmium in the
workplace gave birth to infants with below-normal birth weights, but  no
congenital malformations were noted.

     Data from animal studies are also limited. Prigge (1978) exposed
rats to concentrations of 0.2, 0.4, or 0.6 mg/m3 cadmium for 24 h/day
during pregnancy and observed decreased maternal weight gain in all
groups and decreased fetal weight in the high-dose group. No teratogenic
effects were noted. Similarly, Cvetkova (1970) reported that exposure of
pregnant rats on gestational days 1 to 20 to aerosols of cadmium sulfate
(about 3 mg/m3) caused decreased pup weight, but no teratogenic or
embryotoxic effects. Baranski (1984. 1985) exposed female rats to 0.02
or 0.16 mg/m3 of cadmium oxide (5 h/day, 5 days/week, corresponding to
average levels of 0.004 or 0.033 mg/m3) for 5 months preceding and then
continuing during mating and gestation. No evidence of fetotoxicity or
teratogenicity was noted, but signs of impaired neurobehavioral
development (decreased exploratory activity and slowed acquisition of
conditioned reflexes) were detected in offspring from dams at both dose
levels.

     Reproductive effects.  Baranski  (1985) exposed female rats to
cadmium oxide in air at concentrations of 0.02, 0.16, or 1.0 mg/m3,
5 h/day, 5 days/week, for 4 to 6 months, then continued the exposure
through breeding and gestation. This corresponds to average exposure
levels of about 0.003, 0.02, or 0.15 mg/m3, respectively. No effects on
fertility were observed except at the highest dose, which was directly
toxic to the dam. No studies were located on reproductive effects of
inhalation exposure to cadmium in humans.

     Genotoxic effects.  There is mixed evidence that cadmium compounds
may have mutagenic and genotoxic potential  (EPA 1985b, Blinder and
KJellstrom 1986). However, no dose-response data on the frequency of
genotoxic effects in animals or humans exposed by  inhalation were
located.

-------
                                             Health Effects Summary   13

     Cancer.  There is adequate evidence from studies in animals to
conclude that chronic inhalation exposure to CdCl2 is associated with
increased frequency of lung tumors (EPA 1985b). Takenaka et al. (1983)
exposed rats to aerosols of CdCl2 at concentrations of 0, 12.5, 25, or
       "J         *   "
50 jjg/m-* for 18 months and observed a dose-related increase in primary
lung carcinoma frequency of 0, 15, 53, and 71%, respectively.
Preliminary results indicate that intratracheal instillation of high
doses of cadmium sulfide may also increase lung tumors in the rat,  but
inhalation exposure to CdO, CdCl2, CdS04, or CdS for 40 to 60 weeks has
not been observed to increase lung tumors in hamsters or mice (Heinrich
et al. 1986).
     Some epidemiological studies in humans exposed to cadmium provide
limited evidence that inhaled cadmium is a lung carcinogen. Thun et al.
(1985) reported that mortality from respiratory cancer tended to
increase in a dose-dependent fashion in workers with cumulative exposure
levels of <585, 585 to 2,920, and >2,920 (mg/m3)-days, although the
increase was statistically significant only in the high-dose group.
These exposures correspond to time-weighted daily average levels of 168,
727, and 2,522 pg/m-*, respectively. This observation is complicated by
the fact that workers may have been exposed to other chemicals,
including arsenic, and exposure levels to both cadmium and arsenic were
higher in previous years than in more recent years. Although some
researchers have concluded that the observed excess in lung cancer is
more likely to be due to arsenic than cadmium exposure (White 1985, Lamm
1987), Thun et al. (1985) considered possible confounding by arsenic,
and they found that arsenic exposure could not explain the observed
excess in lung cancer.
     EPA (1985b) has calculated unit risk values (the increase in risk
of lung cancer associated with lifetime exposure to a concentration of 1
/ig/m3) from both the animal data (Takenaka et al. 1983) and the human
data (Thun et al. 1985). The resulting values are 9.2 x 10*2 and 1.8 x
10*3, respectively. Because of the considerable uncertainty in
estimating cancer risk at very low doses, these values are intentionally
derived in a conservative fashion; that is, true cancer risks could be
lower but are unlikely to be higher.
     Several studies have noted an increased frequency of prostate
cancer in cadmium-exposed workers, but other studies have not observed
this effect. The evidence at this time for cancer occurrence is
inadequate to conclude that cadmium is a prostate carcinogen (EPA
1985b).

2.2.1.2  Oral
     The toxic effects of oral cadmium exposure have been well studied
in animals, and a significant body of data from exposed humans has also
been accumulated. Figures 2.3 and 2.4 summarize results of a number of
reports which provide information on  the characteristic short-term and
long-term health effects of oral exposure to cadmium.
     Lethality.  In humans, most severe cases of oral cadmium  toxicity
have been associated with ingestion of foods or fluids contaminated by
storage in cadmium-plated containers. Death is usually due to  excessive
fluid loss from vomiting and diarrhea. Lethal doses  in humans  have been

-------
 14    Section  2
  ANIMALS
 (mg/kg/day)

 1000 i-
  100
   10
  10
  01
 001
0001 L-
   •  MOUSE. LD,

   •  RAT GUINEA PIG. LOU
   O  RAT TESTES. ACUTE
   •  RAT TERATOGENICITY GESTATION
   •  RAT. DECREASED PUP WEIGHT GESTATION
-  •  RAT DECREASED FETUSES/DAM. 6 WEEKS
  O  RAT FERTILITY. 50-70 DAYS
  •  RAT. PROTEINUHIA. 6WEEKS
  O  RAT PROTEINURIA 24 WEEKS
- •  RAT BREEDING FAILURE. 2 GENERATIONS
        •  RAT. NEUR06EHAVORAL DEVELOPMENT. S WEEKS PLUS GESTATION
     -  •  RAT. HYPERTENSION  18 MONTHS
        O  RAT. NEUROBEHAVORAL DEVELOPMENT 5 WEEKS PLUS GESTATION
               • LOAEL IN ANIMALS
               O NOAEL IN ANIMALS
                                  A LOAEL IN HUMANS
                                  A NOAEL FOR HUMANS
                                                                 HUMANS
                                                                (mg/kg/day)

                                                                1000 r
                                                                      100
                                                                      10
                                                                      o i
                                                                     001
                                                                    0001
                                                                            A ACUTE LETHALITY
                                                                            A  Gl IRRITATION ACUTE
                                                                          EMETIC THRESHOLD
                                                                          ACUTE


                                                                          BONE RENAL DISEASE
                                                                          CHRONIC
                                                                               RENAL INJURY.
                                                                               CHROMC
      fwctton of
         to ft* tot tar • dHUMtan of 9m «PKM fraqnncy 4 ram *HM to an


                   Fig. 2J.  Effects of cadmium—oral exposure.

-------
                                                       Health  Effects Sunnary    15
ACUTE INTERMEDIATE CHRONIC
(S14DAYS) [15-364 DAYS) (2365 DAYS)
DEVELOP- TARGET TARGET HEPRO- TARGET
LETHALITY MENTAL ORGAN ORGAN DUCTION ORGAN
CANCER
(mg/kg/day)
lOOOi-
   100
    10
   1 0
   0 1
  001
 0001 -
00001
:"   I
                     r, TERATOGENICITY
                                 r. PROTEINURIA
                                         • r. FERTILITY
        r. NEURO-
        BEHAVIORAL
        DEVELOP-
        MENT
                                                                   • r. HYPERTENSION
                                                                   [RENAL DISEASE a
                                                                   A

                                                                   I
         r RAT         A LOAEL IN HUMANS  • LOAEL IN ANIMALS   I   MINIMAL RISK LEVEL
        m MOUSE      A NOAEL IN HUMANS  O NOAEL IN ANIMALS   |   FOR EFFECTS OTHER
        g GUINEA PK3                                        J,  THAN. CANCER
                 Fig. 2.4.  Lereb of significant exposure for cadmium—oral.

-------
 16    Section 2

 reported to  range  from 1,500 to 8,900 mg (CEC  1978), corresponding to
 doses of about  20  to  130  mg/kg in a 70-kg adult.  In animals  (mouse,  rat,
 and guinea pig), most acute  oral LD50 values for  CdCl2 and cadmium oxide
 range from 50 to 300  mg/kg  (CEC 1978).

      Systemic effects.  Oral exposure to cadmium  may result  in adverse
 effects  on a number of tissues,  including kidney, liver, bone, testes,
 the immune system, and the cardiovascular system.

      Following  acute  exposures to high doses,  the gastrointestinal  tract
 is  the principal target tissue,  with typical symptoms in humans
 including nausea,  vomiting,  and diarrhea.  Based on a review  of the
 literature,  The Commission of the European Communities (CEC  1978)
 estimated that  the emetic threshold in humans  ranged from 3  to 90 mg,
 and that severe (but  nonlethal)  effects  could  be produced by doses of 10
 to  326 mg. On this basis, the acute oral NOAEL in adults may be
 estimated to be about 40 Mg/kg.  and the  LOAEL  about 140 /igAg-
      Following  longer-term exposure to lower levels of cadmium, the
 kidney is  generally considered to be  the most  sensitive tissue, and
 evidence of  decreased renal  reabsorption of low-molecular-weight
 proteins or  other  filtered solutes is the  most reliable end  point of
 renal injury. Kotsonis  and Klaassen (1978) supplied rats with drinking
 water containing 0, 10, 30,  or 100 mg/L  of cadmium (as CdCl2). This
 corresponded to average doses of 0,  1.2,  3.1,  or 8.0 mg/kg/day.
 Proteinuria  was observed after 6 weeks of  exposure in the 30 and
 100 mg/L groups, but  no proteinuria was  detected in the 10 mg/L group
 after 24 weeks.  This  identifies  a dose of  about 1.2 mg/kg/day as a NOAEL
 and 3.1  mgAg/day as  a  LOAEL in  animals.

      In  humans,  many  studies  have reported low-molecular-weight
 proteinuria  in association with  elevated levels of cadmium exposure
 (Friberg et  al.  1974,  CEC 1978).  Dose-response data from such studies
 are frequently lacking, however,  and  exposure has been estimated by
 measuring  the cadmium burden  in  kidney or  liver.  For example, Roels et
 al. (1981a,  1983) studied 309  workers  in Belgium who had been exposed to
 cadmium  in the workplace.  They estimated that a concentration of 216
 Mg/g  in  the  renal cortex would affect at least 90% of the exposed
 workers.  This is consistent with the  earlier estimate by Friberg et al.
 (1974) that most humans will  not experience kidney damage until the
 concentration of cadmium in  the  renal cortex exceeds 200 /ig/g.

     Assuming a value of 200  ;*g/g ««  the critical concentration in renal
 cortex,  Friberg et al.  (1974)  employed toxicokinetic data on typical
 cadmium  absorption (4.5%)  and excretion  (0.01% of total body burden per
 day) to  calculate that oral  intake  of 0.35 mg/day (0.005 mg/kg/day)
would reach  the critical concentration in  kidney after 50 years of
 exposure. This calculated value  is  in good agreement with direct
 estimates of the average daily dietary intake  (about 0.6 mg/day) in
patients suffering from cadmium-induced  toxicity in Japan (Yemagata and
 Shigematsu 1970),  and the  estimate  of CEC  (1978)  that 0.2 mg/day is the
NOAEL for proteinuria in chronically  exposed humans.

     More recently, KJellstrom (1986a) reviewed a number of
epidemiological  studies and concluded that average oral exposures of
about 0.2 mg/day will  cause  tubular proteinuria in about 10% of an

-------
                                             Health Effects Summary   17

exposed population by.age 45. Using mathematical toxicokinetic models to
extrapolate to lower exposure levels, a dose of 0.05 mg/day was
estimated to cause tubular proteinuria in about 1% of an exposed
population after 45 years of exposure.

     Another effect of potential concern in chronic cadmium exposure is
hypertension. This effect has been reported in rats exposed to
concentrations of around 10 jtmol/L in drinking water (about
0.1 mg/kg/day) for 18 months, although the effect was not apparent at
higher doses (Kopp 1986) .  The importance of cadmium in human
hypertension is not clear. Above-average concentrations of cadmium in
kidney were noted in humans who died from hypertensive disease
(Schroeder 1965),  but groups of humans known to be exposed to cadmium
usually do not have above-normal incidence of hypertension (Shigematsu
et al. 1981, Staessen et al. 1984).

     Developmental tozicity.  Cadmium exposure has not been shown to
cause developmental effects in humans (CEC 1978, Bernard and Lauwerys
1984). In animals, parenteral administration of cadmium compounds
results in marked embryotoxicity and teratogenicity, but these effects
are not generally observed following oral exposure. For example, Pond
and Walker (1975)  exposed pregnant rats to 200 ppm CdCl2 in the diet
(about 15 mg/kg/day) and observed decreased pup weight but no
teratogenicity or embryotoxicity. However, Baranski (1985) reported
fused or absent legs in fetuses of rats dosed by gavage with 40 mg/kg of
CdCl2 during pregnancy. In addition, several other studies by Baranski
suggest that cadmium exposure during gestation may impair neurological
development in the fetus.  Baranski et al. (1983) reported reduced
exploratory activity and decreased motor ability in offspring of rats
dosed by gavage with 0.4 or 4 mg/kg/day for 5 weeks prior to and then
continuing during gestation. No effects were detected in offspring from
dams dosed with 0.04 mg/kg/day. Similar neurobehavioral changes were
reported by Baranski (1986) in offspring of rats supplied with drinking
water containing 60 mg/L of CdCl2 (a dose of about 9 mg/kg/day) during
gestation. The biological significance of these effects is not known.
     Reproductive effects.  Reproductive effects of cadmium have not
been reported in humans. In animals, parenteral administration of high
doses often produces severe injury to the gonads, especially in males,
and this can lead to impaired reproduction or total sterility. Following
oral exposure, effects are generally much less severe. For example, no
injury to testes or impairment of male fertility was observed in rats
given single oral doses of 25 to 50 mg/kg, although effects were
observed at doses of 100 or 150 mg/kg (Kotsonis and Klaassen 1977). No
effects on sperm or fertility were noted in male rats supplied with
drinking water containing 68.8 mg/L (about 7 mg/kg/day) for 70 days
(Zenick et al. 1982), and no impairment of fertility was noted in female
rats treated by gavage with doses up to 4 mg/kg/day for 5 weeks
preceding and then continuing through gestation (Baranski et al. 1983).
Sutou et al. (1980) exposed both male and female rats to doses of 0.1,
1.0, or 10 mg/kg/day by gavage for 6 weeks. No significant effects were
observed on several Indices of fertility (copulatory and impregnating
ability of males or pregnancy ratio and efficiency in females), although
the number of live fetuses per dam was decreased in the high-exposure
group. Schroeder and Mitchner (1971) reported breeding failure in rats

-------
 18    Section  2

 exposed for two  generations  Co  water  containing 10 mg/L  (about  1
 n>gAg/day) , and  Willis  et  al.  (1981)  reported decreased  reproductive
 success in rats  fed cadmium  (about  5  to  10 mg/kg/day) in the diet  for
 four  generations.

      Genotoxicity.   There  is mixed  evidence from in vitro studies  in
 bacterial and eukaryotic test systems  that cadmium compounds have
 mutagenic and genotoxic activity  (EPA  1985b, Elinder and Kjellstrom
 1986).  but no in vivo studies providing  oral dose-response data on the
 appearance of genotoxic effects in  exposed animals or humans were
 located.

      Cancer.  A  number  of  chronic studies have been performed on the
 carcinogenic  potential  of  cadmium compounds given to animals in food or
 water,  and all have  yielded  negative results (Schroeder  1965, Malcolm
 1972, Levy and Clark 1975, FDA  1977, Loser 1980).  Similarly,
 epidemiological  studies in humans exposed to elevated levels of cadmium
 in water or food do  not indicate that  cadmium is a carcinogen by the
 oral  route (Bernard  and Lauwerys 1986).

 2.2.1.3  Dermal

      Cadmium  compounds  have  not been observed to cause significant
 health effects when  exposure is by  the dermal route.

 2.2.2  Biological Monitoring as a Measurement of Exposure and Effects

 2.2.2.1  Exposure

      Cadmium  levels  in  blood, urine, hair, feces,  liver, and kidney have
 all been investigated and  used  as biological indicators of exposure to
 cadmium. A discussion of the utility and limitations of each for human
 biomonitoring is provided  below.

      Blood.    It  is generally accepted  that cadmium levels in whole blood
 reflect mainly recent exposure  to cadmium rather than body burden
 (Shaikh and Smith 1984, Ghezzi  et al.  1985, Rogenfelt et al. 1984),
 although recent  studies indicate that blood cadmium levels may have a
 greater dependence on body burden than was previously believed
 (Rogenfelt et al. 1984, Ghezzi  et al.  1985).

     Concentrations of  cadmium  in blood in normal  populations range from
 about 0.4 to  1.0 Mg/L for  nonsmokers and 1.4 to 4.0 Mg/L for smokers
 (Elinder 1985b,   Chmielnicka  and Cherian 1986,  Rogenfelt et al.  1984,
 Sharma et al.  1982). Values  in  occupationally exposed populations have
been observed to range  from  10  to 100 Mg/L (Friberg et al.  1974,
Rogenfelt et al.  1984).

     Based on a  study of occupationally exposed individuals, Rogenfelt
et al. (1984)  suggested that average blood cadmium levels over a period
of years should not exceed 10 Mg/L cadmium in order to prevent renal
dysfunction.

     Urine.   Although cadmium levels in urine vary somewhat in response
 to recent exposures, average urinary excretion levels are generally
considered to be a useful  indicator of total body  burden of cadmium
 (Chmielnicka and Cherian 1986,  Nomiyama 1986,  Bernard and Lauwerys 1986,

-------
                                             Health Effects Summary   19

Shaikh and Smith 1984),  except when the critical level for renal damage
has been reached. At this time, there is a sharp increase in urinary
cadmium excretion due to release of intrarenal cadmium along with
reduced renal raabsorption of cadmium (Shaikh and Smith 1984, Ellis
1985, Friberg 1984). Thus, urinary cadmium levels should be used in
conjunction with the results of other tests of renal function to
evaluate cadmium exposure (Shaikh and Smith 1984).  Urinary cadmium
levels of 1.32 to 13.88 pg/g creatinine were found in exposed workers
(Ghezzi et al. 1985). In the general population, average urinary cadmium
is around 0.35 pg/g creatinine (Lauwerys et al. 1976), and values above
2 pg/g creatinine are exceedingly rare (Lauwerys and Halcom 1985).
     Feces.  Since dietary cadmium is poorly absorbed in the
gastrointestinal tract,  fecal cadmium may be used as a direct indicator
of its daily dietary intake (Shaikh and Smith 1984, Friberg 1984).  This
reflects only recently ingested cadmium and, therefore, is not a good
indicator of total cadmium exposure, especially in occupationally
exposed individuals (Shaikh and Smith 1984).
     Hair.  Cadmium in hair has sometimes been used as an indicator of
cadmium exposure. However, significant amounts of exogenous cadmium may
adsorb to hair and become incorporated into the hair matrix, making it
difficult to distinguish between cadmium incorporated into hair from the
body burden and externally adsorbed cadmium (Shaikh and Smith 1984, Huel
et al. 1984). Because the adsorbed cadmium is very difficult to remove
by washing, hair cadmium is generally considered to be a poor indicator
of adsorbed dose, especially under occupational conditions  (Tsalevvand
Zaprianov 1983, Singerman 1984). On the other hand, Huel et al. (1984)
showed a significant correlation between hair cadmium levels of exposed
mothers and their newborn infants. Assuming that newboras would have
little chance of external cadmium exposure, this correlation indicates
that in some cases, hair levels may be more useful indicators of body
burden than previously believed.
     Tissues.  Cadmium is strongly accumulated  in liver and kidney, and
concentrations of cadmium in these tissues may be measured  in vivo by
neutron activation analysis (Ellis 1985). Levels tend to increase  in
both tissues as a function of age and of exposure level. Typical renal
burdens in nonexposed individuals in North America at age 50 are usually
around 25 to 40 pg/g, and values in liver range from'l to 3 Mg/g
(Elinder 1985b). In workers or other people who have been exposed  to
cadmium, levels in kidney and liver commonly range up to 300 and 120
Mg/g, respectively  (Friberg et al. 1974, CEC 1978, Ellis et al.  1980).
The cadmium content of kidney begins to decline around age  60, or  upon
the development of renal disease (Friberg 1984, Scott and Chettie  1986).

     Ellis (1985) Investigated the dose-response relationship between
renal and hepatic cadmium levels and the probability of renal
dysfunction. Using mathematical models,  the author estimated that  about
half of an exposed population would experience  kidney dysfunction  when
the total kidney cadmium burden reached  35 mg  (equivalent to about 350
Mg/g in renal cortex).
     Because neutron activation analysis  involves  complex and costly
equipment, this procedure is not well suited to routine or  repeated

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20   Section 2

monitoring of potentially exposed individuals (Shaikh and Smith 1984,
Scott and Chettle 1986, Ellis 1985, Friberg 1984).

2.2.2.2  Biological effects

     Renal dysfunction, primarily impaired tubular  reabsorption of
filtered solutes, is the primary toxic effect of chronic cadmium
exposure. This may be measured by the appearance in urine of one or more
of a number of substances, including 02-microglobulin,  retinol-binding
protein, metallothioneln, amino acids, enzymes,  and glucose.  Excretion
of excess low-molecular-weight proteins and solutes is  associated with
decreased tubular reabsorption, whereas an increased excretion of high-
molecular-weight proteins reflects glomerular dysfunction.  A brief
discussion of the utility and limitations of each of these parameters  as
biological indicators of the effects of cadmium is  provided below.

     Urinary microglobulin.  02-Microglobulin is a  medium-weight
(11,800) protein whose rate of urinary excretion is considered a
sensitive indicator of tubular renal dysfunction (Nogawa 1984, Scott and
Chettle 1986, Shaikh and Smith 1984, Ormos et al. 1985, IUPAC 1984).
However, since 02-microglobulin excretion can be caused by other renal
diseases, this assay is not specific for cadmium-induced injury (Shaikh
and Smith 1984, Scott and Chettle 1986). Urinary loss of 02-microglobulin
has also been reported to increase with age even in the absence of renal
dysfunction (Nogawa 1984). In addition, 02-microglobulin degrades
rapidly at 37°C at pH values below 5.5, so special  attention must be
given to the pH in the analysis for this protein (IUPAC 1984, Topping et
al. 1986, Shaikh and Smith 1984).

     Another low-molecular-weight protein suggested as  an early
indicator of proximal tubule damage is al-microglobulin (Tohyama et al.
1986). It was reported that the urinary excretion of al-microglobulin is
closely associated with urinary cadmium and other indices of renal
dysfunction. The authors suggest that this protein  be used together with
others in screening for renal dysfunction due to environmental cadmium
exposure.

     Urinary re tinol-binding protein.  Retinol-binding protein is also
considered a sensitive, but nonspecific, indicator  of decreased tubular
reabsorption (Shaikh and Smith 1984, IUPAC 1984, Topping et al. 1986).
Topping et al. (1986) reported that retinol-binding protein and
02-microglobulin are of approximately equal sensitivity and specificity
in detecting tubular proteinuria in cadmium-exposed subjects, but the
International Union of Pure and Applied Chemistry (IUPAC 1984) suggested
that retinol-binding protein may be a more suitable index of tubular
damage because of its greater stability. However, there is no consensus
that retinol-binding protein is a better indicator  of cadmium effects on
the kidney. IUPAC (1984) suggested that both proteins should be
measured. Ormos et al. (1985) reported fluctuations in levels of both
proteins in exposed populations and suggested repeated sampling and
analyses to obtain reliable results.

     Urinary metallothionein.  Metallothionein synthesis is increased in
response to cadmium exposure, and urinary metallothionein correlates
with cadmium concentrations in liver, kidney, and urine (Shaikh and
Smith 1984). Although metallothionein synthesis may also be induced by

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                                             Health Effects Summary   21

heavy metals other than cadmium, and even by nonmetallic toxicants and
by hormones, good correlations have been observed between urinary
metallothionein and urinary cadmium (Bernard and Lauwerys 1984,  Shaikh
and Smith 1984). It has been suggested, therefore, that measuring
urinary metallothionein is equivalent to measuring urinary cadmium
(IUPAC 1984). Urinary metallothionein increases greatly, however, once
the critical cadmium concentration in the kidney is reached.

     Enzymes and other proteins in urine.  Several other proteins have
been suggested as biological markers for detecting incipient renal or
liver damage resulting from cadmium exposure. Bomhard et al. (1984)
studied urinary excretion of lactate dehydrogenase and glutathione
transferase in cadmium-exposed rats and found a significant increase in
output of both enzymes without an increase in total urinary protein
excretion. The authors concluded that these enzymes might be useful
markers for monitoring exposed humans. Other enzymes considered as early
indicators of renal damage include alkaline phosphatase, glutamic-
oxaloacetic transaminase, glutamic-pyruvic transaminase, and carbonic
anhydrase C. There is no consensus on which enzyme is the optimal
indicator of renal damage (Shaikh and Smith 1984), and as noted above,
increases in urinary levels of these enzymes are not specific indicators
for cadmium-induced renal damage.

     Amino acids in urine.  There are conflicting reports on the value
of aminoaciduria as an indicator o'f cadmium toxicity. Some researchers
found aminoaciduria to be one of the earliest signs of renal toxicity,
while others found it to be a less sensitive indicator than proteinuria
(Shaikh and Smith 1984).
     In summary, there appears to be no biological indicator for cadmium
toxicity that is entirely adequate when considered alone. Measuring
several parameters, some specific for renal dysfunction and some
specific for cadmium exposure, can together provide a good indication of
the toxic effects of cadmium exposure. Lauwerys and Halcom (1985)
suggest that monitoring should involve periodic measurement of urinary
and blood cadmium levels, along with several tests of renal dysfunction
such as glucosuria, proteinuria, albuminuria, 02-nicroglobinuria, or
urinary rentiol-binding protein. Shaikh and Smith (1984) suggest that
the most reasonable parameters to measure are urinary cadmium,
metallothionein, and £2-nicroglobulin.
2.2.3  Environmental Levels as Indicators of Exposure and Effects

2.2.3.1  Level* found in the environment
     Cadmium occurs naturally in the earth's crust, and low levels  of
cadmium are found in most waters. Typical concentrations in groundwater
and drinking water are 1 pg/L or less  (Meranger et al.  1981. Page  1981),
which may be present as the free cadmium ion or adsorbed to suspended
particulate matter. Groundwater concentrations may be increased  by
seepage from hazardous waste sites, and drinking water  levels may be
increased by leaching of cadmium from  plumbing fixtures and solder
(especially by  soft or acidic water).
     Major sources of cadmium emissions  into air  include burning of
fossil fuels (coal, oil, and gasoline) and  incineration of  municipal
wastes. The usual form of cadmium  in  ambient air  is  cadmium oxide,

-------
22   Section 2

adsorbed to suspended particulate matter of varying sizes.  Typical
atmospheric concentrations range from about 1 to 5 ng/m3 in rural areas
to between 5 and 40 ng/m3 in urban areas (Elinder 1985a).  Levels of 500
ng/m3 or higher may occur in the vicinity of specific industries such as
nonferrous metal smelters, although such levels are now less common
because of the increased use of emission controls (EPA 1981, Bernard and
Lauwerys 1986).

     Typical soil levels of cadmium range from about 100 to 1,000 pg/kg,
with an average value of about 260 pg/kg (Carey 1979). Cadmium in soils
and dusts may be in the form of the oxide or as ionic complexes with
other cations, anions, and organic soil constitutents. In the vicinity
of airborne emission sources (roadways, smelters, coal-fired burners,
etc.), cadmium levels may be significantly higher (Carey 1979, EPA 1981,
Baltrop 1986). Soil levels of cadmium are also increased by the disposal
of municipal sludges which tend to be high in cadmium.

2.2.3.2  Human exposure potential

     Typically, the most important source of cadmium exposure for humans
is ingestion of food. For people in the United States, values of about
15 to 30 pg/day are common (EPA 1981, Gactrell et al. 1986). Much of
this comes from plant material (especially grains and cereals) which
takes up cadmium from the soil. Shellfish may also be a significant
source of dietary cadmium. Typical dietary intake is about one-tenth the
minimum level that is considered to be of health concern.

     Smoking is also an important source of cadmium exposure.
Individuals who smoke one pack per day typically have cadmium blood and
body burdens approximately twice as high as nonsmokers (Lewis et al.
1972, Ellis et al. 1979, Hammer et al. 1973, Sharma et al.  1983).

     Occupational exposures to airborne dusts and fumes of cadmium can
pose a significant health risk. This exposure may extend to residents
living in the vicinity of major sources of airborne emissions. Chronic
workplace exposure to levels of 50 to 200 fig/a? has been reported to
cause renal Injury and emphysema, as well as increased risk of lung
cancer (Friberg et al. 1974). Typical levels in ambient air (0.003
    3) are of relatively low health concern.
2.3  ADEQUACY 07 DATABASE

2.3.1  Introduction
     Section 110 (3) of SARA directs the Administrator of ATSDR to
prepare a toxicological profile for each of the 100 most significant
hazardous substances found at facilities on the CERCLA National
Priorities List. Each profile must include the following content:
    "(A)  An examination, summary, and Interpretation of available
          toxicological information and epidealologic evaluations on a
          hazardous substance in order to ascertain the levels of
          significant human exposure for the substance and the
          associated acute, subacute, and chronic health effects.
     (B)  A determination of whether adequate information on the health
          effects of each substance is available or in the process of

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                                             Health Effects Summary   23

          development  to determine  levels  of exposure which present a
          significant  risk to  human health of acute, subacute, and
          chronic health effects.

      (C)  Where appropriate, an  identification of toxicological testing
          needed to  identify the types or  levels of exposure that may
          present significant  risk  of adverse health effects in humans."

      This section identifies gaps in current knowledge relevant to
developing levels of significant exposure  for cadmium. Such gaps are
identified for certain health  effects end  points (lethality,
systemic/target organ  toxicity,  developmental toxicity, reproductive
toxicity, and carcinogenicity) reviewed in Sect. 2.2 of this profile in
developing levels of significant exposure  for cadmium, and for other
areas such as human  biological monitoring  and mechanisms of toxicity.
The present section  briefly summarizes the availability of existing
human and animal data, identifies data gaps, and summarizes research in
progress that may fill such gaps.

      Specific research programs  for obtaining data needed to develop
levels of significant  exposure for cadmium will be developed by ATSDR,
NTP,  and EPA in the  future.

2.3.2  Health Effect End Points

2.3.2.1  Introduction  and graphic summary

      The availability  of data  for health effects in humans and animals
is depicted on bar graphs in Figs. 2.5 and 2.6, respectively.

      The bars of full  height indicate that there are data to meet at
least one of the following criteria:

 1.   For noncancer health end points, one  or more studies are available
      that meet current scientific standards and are sufficient to define
      a range of toxicity from no effect levels (NOAELs) to levels that
     cause effects (LOAELa or FELs).

 2.  For human carcinogenicity,  a substance is classified as either a
      "known human carcinogen" or "probable human carcinogen" by both EPA
     and the International Agency for Research on Cancer (IARC)
      (qualitative),  and  the data are sufficient to derive a cancer
     potency factor  (quantitative).

 3.  For animal carcinogenicity, a substance causes a statistically
     significant number  of tumors in at least one species and the data
     are sufficient  to derive a  cancer potency factor.

 4.  There are studies which show that the chemical does not cause this
     health effect via this exposure route.

     Bars of half height indicate that "some" information for the end
point exists, but does not meet  any of these criteria.

     The absence of  a  column indicates that no information exists for
that end point and route.  In some cases, information for one route of
exposure may not be  applicable for developing levels of significant
human exposure, even if  it is available, and this is indicated by a
fully shaded cell on the graph.

-------
                                               HUMAN  DATA
                                                                                                                                      t/i
                                                                                                                                      8
                                                                                                                                      rt
                                                                                                                                      a
                                                                                                                     SUFFICIENT
                                                                                                                    INFORMATION*
                                                                                                               J
                                                                                                                        SOME
                                                                                                                    INFORMATION
                                                                                                                          NO
                                                                                                                    INFORMATION
                                                                                                         ORAL
                                                                                                    INHALATION
                                                                                               DERMAL
LETHALITY        ACUTE     INTERMEDIATE    CHRONK    DEVELOPMENTAL  REPRODUCTIVE  CARClNOOCNICfTt
           ^	/     Toxicrrv        TOXWITY
                      SYSTEMIC TOXICITV

                       'Sufficient information exists to meet at toast one of the criteria tor cancer or noncancer end points.

                          Fig.  2.5. Availability of information on health effects of cadmium (human data).

-------
                                              ANIMAL  DATA
                                                                                                                SUFFICIENT
                                                                                                               INFORMATION*
                                                                                                                   SOME
                                                                                                               INFORMATION
                                                                                                                    NO
                                                                                                               INFORMATION
                                                                                         DERMAL
LETHALITY
               ACUTf      INTERMEDIATE    CHNONK   DEVELOPMENTAL HEPflODUCTIVE  CARCWOOEMCITV
              —	/    TOXICITV        TOXICITV
                    SYSTEMIC TOXICITV

                     'Sufficient information exists to meet at least one of the criteria for cancer or noncancer end points.

                        Fig. 2.6.  Availability or information on health effects of cadmium (animal data).

-------
 26   Section 2

 2.3.2.2  Description of highlight* of graphs

     There  is a massive database regarding the health effects of
 cadmium. In humans, the majority of studies have involved individuals or
 groups exposed to major sources of airborne cadmium emissions.
 Unfortunately, quantitative estimates of exposure levels are not
 available for many of these studies. In animals, effects following oral
 exposures have generally been more thoroughly investigated than those
 following inhalation exposure. Dermal exposure is not considered to be
 of  significant health concern.

     Although it is generally agreed that the kidney is the most
 sensitive organ following chronic low-level exposure to cadmium, there
 is  still some uncertainty regarding the critical concentration of
 cadmium in  the renal cortex, and there is also a range of uncertainty
 regarding the maximum chronic daily exposure level that will not result
 in  renal injury. Lung carcinogenicity following inhalation exposure to
 CdCl2 has been documented in animals, but the lung carcinogenicity of
 other cadmium compounds is not yet defined. There have been a number of
 epidemiological studies of the risk of lung cancer in humans as a result
 of  chronic  cadmium exposure (mostly to CdO), but the evidence is limited
 and sometimes conflicting. Most other end points of concern
 (hypertension, obstructive lung disease, hepatotoxicity, and
 immunotoxicity) have also been well studied, although additional
 research is required in some cases to define the dose-response
 relationship more clearly. Developmental and reproductive effects of
 cadmium in  animals have been studied mostly after parenteral dosing, but
 only limited oral and inhalation data are available, and these effects
 have not been well studied in humans.

 2.3.2.3  Summary of relevant ongoing research

     Cadmium continues to be the subject of vigorous research in many
 laboratories across the United States, Europe, and Japan. In this
 country,  cadmium research is sponsored by a number of industry, state,
 and federal agencies, and it is not possible to list all of the research
 activities  supported by these groups. Table 2.1 summarizes ongoing
 research projects related to cadmium that are presently funded by the
 National Institutes of Health (NIH) or the International LeadxZinc
 Research Organization (ILZRO). These projects may be expected to produce
 valuable new information on the toxicokinetics, health effects, exposure
 levels, and monitoring options for cadmium.

 2.3.3  Other Information Reeded for Human Health Assessment

     Although cadmium toxicity has been extensively investigated in both
 animals and humans, a number of important areas require additional
 research in order to improve our understanding of cadmium toxicity.

 2.3.3.1  Pharmacokinetics and mechanisms of action

     In spite of considerable information on the actions of cadmium in
higher animals and man,  there remain Important gaps in our understanding
of the toxicology of this metal. The biochemical mechanism by which
cadmium leads to the lesions observed in the target organs has not been
clarified.  Plausible mechanisms for which there are supporting data

-------
Health Effects Summary   27

Prvnapal
IBVCMIfllOT
Bcalky. PJ
BurchwL S W
Chenu. C
Clarboo. T W
Diamond, CL
EUO.K.
Foulkea.E.C
Fount*. EC
Fowler. B A
Garvey. JS
Coyer. R
Coyer. R.A
Gray. I
Hadtey. WM
HU1.B.A.
Hoffer. BJ
JamalLLS
Jootti M M
KueUUBi G
Kluoen.C.D
Kuhnen.P.M
Lauweryi, R.
MirooxCJ*
Institutional
affiliation
North Carolina
Sute Unncmiy
Uoiveniry of
New Mexico
Univemty of
Wenera Ontario
Univenity of
Rochester
Uaivenily of
Rocbener
la Vivo Synemf.
Houston. Texat
Uoivemty of
Ciaanaau
University of
ClDGUUUtl
NIEHS. NIH
Syracuse
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Uaivemty of
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Uaivemty of
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Georgetown
Univemty
Uaivemty of
New Mexico
Uaivemty of
Vermont
Uuvemty of
Color MO
SL Joho'i
Uaivemty
Vandermll
Univenity
Uodoa School of
Hypcoe. United Kinfdoo
Uaivemty of
•Unas*
CneWeeten
R*eer*e
Uamnqr
Unmmty Cuhotaqae
daLoBvaia, Bdpam
Uuvemry of
North Caroiini.
Chapel HiU
DeKnpUoo of laemrch
AccumuUuoa tod effeeti of trice meuli. including i^mium. o" ninfil
mrtihnlirm in rabbit ICOK rote in cataract formation
ImmntKuminty of cadnuun and other tfeou. cell lypet affected.
imrhanum of action
Renal loxicity of chronic expanire to cadminm
ToxMokinetici of uptake, donnbution. effecu oa rtpraduction.
development* behavior
Effect of *•"*•—— on renal metabolam and trampon in rau
Doaerfiponae toatyta in cadmium worken

reabaorptiott
ofmeuli
Meaaurenxnt of mmallmhionnn (MT) in homaa unmet and ffaudi by
radiaunmaaoaauy (RlAk rate of MT in cadmium —"fc-^TTt
Renal touoty of chronjc exposure to *yfninim
Effect of •~*""""i on trace metal •"***I"'ITIT in uver. bdney; cdtalar
toveb of free and bound cadmium, rote of animal dementi on losoty
Effect of cadmium and lead on cellular and Nortmacnl ininiiiii of
wound beahnt
Induction of MT in rat lung, doae-ianeaie. cell lypea. rote in
DFOt0CtlOB lod IflAcWOOB
Effect oiT ndmnim and other meuto oa brmin; •"•^>mn u fc«^^i>^i*^|
Mechanom of cadmium-iaducad cardmouaqr. rote of aluutaaoe
Uaa of cheUlan w reduce cadmium mnnmtmwwii in bdney and ether
U^alwlft flvwHlW fJ ^m^^m^m^ ——^^—^
•MlHia ••••wj <• GBBDuUB WraBn
1
in tale
Fetal exposure to heavy meuhi in urban cnvmnmentc; interaction of
cadmium and BBC in pregnant tmoftcn; rote of one deficiency in to*
bmhwcuht
Reaerva capncny of the bdney

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-------
28    Seccion 2
                                   TaMel.1 (c
Principal
mvenigator
McCany. K S

MenxeL 0 B

Miller. R K

Munhy. R

Mylrae. A A.

Nomiyama. K.

Oberdocmer. G
Oberdocmer. G

Puachetu JB

Rajaaaa. B
SaaadLDR

Saury. BV

Shaikh. Z A.


Shigemauu. 1


Sun. T

Webber, M M

Wiachurch. RA.

Immuuoaal
afTdiatioa
Duke Univenity

Duke Univemty

Univenity of
Roc better
Central State
Univenity
Chicago Stale
Univeniiy
Jichi Medical
School. Japan
Univenity of
Rocbcncr
Univemty of
Rochester
Univenity of
Pituburgb
Selma Univenity
Boctoa Medical
Rca. Institute
Vanderbilt
Umvemty
Univeniiy of
Rhode Ulaad

Radiatwa Effecu
Re*earch Foundation,
Japan
Univemty of
Cincinnati
Univenity of
Colorado
Baltimore City
Hospital

Deacnptioa of research
Regulation of MT gene expression in Chinese hamster ovary (CHO)
cells; conditions of gene unpiificstioa: rate of glucocorucoidi
Lung absorption of trace metals from submicroa paniculate aerosols:
kinetics of removal, transport
Placenta! loueotaneuci of ~«— -- induction of MT. rote of selenium
and one
Pulmonary reponse to metals in rau



Critical concentration of cadmium in the renal cortex

Pulmonary toucny of metals in rau and pnmalec evaluation of lung
permeability; effect of eamptauag agcau on pulmonary cteatanos
Lung retention of cadmium oude and cadmium
olfida in rau and moakays
Inndrnca of renal and skeletal srmnrmslmrs in lead- and cadmium-

Reaal tad hepatic toucuy of heavy meuto in rau



mrtaholmn; labibmoo of spsofk phmynUiprt methyhnnsferaats
Metabolism and toucrty of cadmium in numnahs rote of MT. correlatioo of
unaary MT to tame cadmium in humans: rate of MT in renal toncRy.
cellular nmrrlaniiriH of eadmmm uptake, toueny

latbebdaey


mlarinoihrpi rote of one
Rote of eadmmm in prostate caranogoDOBs: acooa as initiator and/or
pfonotor nodted ui vtuo
Effect of cadmium and lead en immune function in mice: dose-response; metal
dtsuftonaa IB spaafk edl types: latancaoas with BBC, MT

Dau gap"
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-------
                                             Health Effaces Summary   29

include: (1) cadmium.interference with the function of an essential
metal like zinc in some zinc enzyme systems (NATH et al. 1984);
(2) cadmium interference with intracellular calcium homeostasis,  perhaps
by interaction of cadmium with calmodulin, the calcium-binding
regulatory protein (Suzuki et al. 1985); and (3) cadmium binding to
sulfhydryl groups of key cellular enzymes or other essential molecules
(Klaassen et al.  1985, Stacey et al. 1986).
     A second major gap in our present understanding of cadmium
toxicology relates to the uncertainty of concentration-effect
relationships in the target tissue. There is considerable evidence to
suggest that the critical level  is strongly influenced by details of the
exposure conditions, and total tissue cadmium may be a less significant
quantity than the concentration  of the metal in the various cellular
pools, such as metallothionein-cadmium and cadmium bound to other cell
constituents. Additional research is needed to clarify the toxicological
importance of cadmium in these various subcellular compartments. In the
absence of such information, the concept of a critical level in the
target tissue will possess somewhat limited usefulness.

2.3.3.2  Monitoring of human biological samples
     There are a number of useful options for measuring cadmium exposure
in human fluids or tissues. It is usually considered that the most
important determinant of toxicological  injury is the concentration of
cadmium in target tissues such as renal cortex or  liver. While tissue
levels may be measured in vivo by neutron activation analysis, this
procedure is not well suited for routine or repeated monitoring, and
continued efforts to derive methods for estimating tissue burdens  from
blood or urinary values are desirable.
     There are also  a number of  sensitive  tests  to detect  the early
stages  of renal disease associated  with cadmium  exposure, but all  of
these detect injury  which has already occurred.  Research  to  identify
even earlier biomarkers of  incipient  injury to kidney  (and  other  tissues
as well) would be very useful.

2.3.3.3  Environmental considerations
     Cadmium can be  easily  measured in  most environmental samples  with  a
sensitivity  that  is  adequate with  respect to  levels of health concern.
By comparison with  other metals  (e.g.,  arsenic,  mercury,  and chromium),
the chemistry and environmental  fate  of cadmium is relatively simple  and
reasonably  well understood.

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                                                                      31
                 3.  CHEMICAL AMD PHYSICAL INFORMATION

3.1  CHEMICAL IDENTITY
     Cadmium is a naturally occurring metallic element (atomic number
48). Table 3.1 lists the common name, the Chemical Abstracts Service
(CAS) number, molecular formula, synonyms, and identification numbers
for cadmium and a number of cadmium compounds.

3.2  PHYSICAL AND CHEMICAL PROPERTIES
     Pertinent physical and chemical properties of cadmium and the
selected cadmium compounds are listed in Table 3.2. These are stable
compounds with high melting points and low volatility. The solubility of
these compounds in water ranges from quite soluble (cadmium chloride) to
practically insoluble (cadmium oxide).

-------
Table 3.1. Chemical Idcrttty of r •<•.!•• ami ithcud II co^
Ul
ro
to
*-* 5
Identification numbers a

Chemical
name
Cadmium

Cadmium
carbonate
Cadmium
chloride
Cadmium
hydroxide
Cadmium
nitrate
Cadmium
oxide
Cadmium
silicate
Cadmium
tulfale
Cadmium
•ulTide

"ND-
Sourc*.


Synonym(i)
Colkmlal cadmium

Ota vite cadmium
mooocarbonate
Cadmium dichtandc
Dichlorocadmium


Cadmium dimtrate

Cadmium fume
Cadmium monoxide
Cadmium metaiihcate

Cadmium monotulfate

Cadmium yellow
Cadmium moootuliidc
Cadmium orange
Not determined
Adapted from HSDB 1987

Wiswcaier
Formula line notation
Cd CD

CdCO, OVO and -CD-

CdCI, CD G2

CdCOH),

Cd(NO,), ND

CdO CDO

CdSiO,

CdSO« CD S-O4

CdS CDS




EPA
NIOSH Hazardoui
CAS Registry RTECS Waste
7440-43-9 EU9800000 0006

SI 3-78-0 FF9320000 ND

10108-64-2 EVOI75000 ND

21041-95-2

10325-94-7 EVI850000 ND

1306-19-0 EVI930000 0006

13477-19-5

10124-36-4 EV2700000 ND

1306-23-6 EV3I80000 ND




DOT/UN/
NA/IMCO
OHM-TADS Shipping STCC HSDB
7216622 IMCO6I ND" 282
UN2570
ND UN2570 ND 1612

7217229 UN2S70 49 6)S OS ?1R
* *• * **' Ut^U 1 V W V* J VJ * f O .
NA2S70


7217230 UN2S70 ND 276

ND UN2570 ND 1613



7217231 UN2570 ND 274

ND ND ND 1614





-------


laow A*, rays



BMBI aa» unrrnu i



Solubility
Chemical
oame
Cadmium

6
Cadmium carbonate
Cadmium chloride



Cadmium chloride
hemipcntahydrale

Cadmium hydroxide

Cadmium nitrate


Cadmium nitrate
tetrabydratc
Cadmium oudc


Cadmium silicate


Cadmium sulfale

Cadmium sulfide

Molecular
weight
112.41

117 At
I i £.44
183.32



228 34*

14643

23643


30848*

128.40


18849


20847

14446

Melting
point CO
321


321
S68



Transition
point 34'

Decomposition
starts at 1 30
350


59.5

Amorphous 1426
(decomposes at
about 900)
1242
,

1000

1750 at
100 aim
Boiling
point CO
765

ND'

960





NA

ND


132

ND


NA


ND

ND

Density
(g/cm1)
865

4 26

4.047



3327*

479

ND


2455

8.15


493


4691

482

State
Solid

Solid

Solid



Solid''

Solid

Solid


Solid

Solid


Solid


Solid

Solid

Color
Silver-white

White

White



Colorless''

While

Colorless


While

Brown


Colorless


Colorless

Yellow, orange
or brown
Water
(g/IOOcc)
Insoluble

Practically
insoluble
140



.68"

Almost
insoluble
109 at O'C
326 at 60"C

215'

Insoluble


Very slightly
soluble

76 at 0°C

000013

Organic solvents Hammabdity
NA" Powdered cadmium
is flammable
Insoluble ND

Soluble in acetone. ND
slightly soluble in
methanol. elhanol.
insoluble in ether
Soluble in methanol,
slightly soluble in
alcohol
NA NA

Soluble in ether. ND
acetone, alcohol

Soluble in alcohol.
acetone
NA Not flammable


NA NA


Almost insoluble ND
in alcohol, acetone
NA ND













Q
A
B

n'
to
ft
3
Q.
*XJ
S"
10
h-
O
to
t—
tj1
cT
i
"NA - Not available
* Adapted from Farnsworth 1980
'ND - Not determined
4Adapted from Weasl 1985
Source  Adapted from HSDB 1987 unless otherwise noted

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                                                                      35
                         4.  TOXICOLOGICAL DATA
4.1  OVERVIEW
     Cadmium is a potent toxicant by both oral and inhalation exposure.
Dermal exposure to cadmium compounds is not of significant health
concern. The mechanisms of cadmium-induced toxicity are not fully
understood but may involve binding of cadmium to key cellular sulfhydryl
groups, competition with other metals (e.g., zinc and selenium) in
metallo-enzymes, or competition with calcium for binding sites on
regulatory proteins such as calmodulin.
     There are important differences between various cadmium compounds
with respect to their absorption and hence their toxicity. In general,
soluble compounds such as CdCl2 are better absorbed and are more toxic
than highly insoluble compounds such as CdS.
     Acute exposures to high levels of cadmium compounds are highly
irritating to the epithelial cells of the gastrointestinal or
respiratory tract. Other tissues injured by high doses (especially when
given to animals by injection) include liver and testes. The fetus may
also be injured by high parenteral doses. However, high exposures of
this sort are now quite unlikely, even in an occupational setting. The
principal health concern is for chronic low-level exposure to cadmium by
either the oral or the inhalation route.
     Cadmium is absorbed moderately well from the lungs but quite poorly
from'the gastrointestinal tract. The principal excretory route for
absorbed cadmium is the urine. However, urinary excretion is very slow,
for two reasons. First, the large majority of total body cadmium exists
within tissues, tightly bound to metallothionein or other cellular
components. Second, although cadmium in plasma is readily filtered at
the glomerulus, it is nearly all reabsorbed in the proximal tubule,
perhaps in the form of cadmium-metallothionein complex'. Once inside the
cells of the tubule, the cadmium-metallothionein complex  is probably
degraded in lysosomes with the resulting release of free  cadmium  (Webb
and Etienne 1977, Singerman 1984, Nomiyama  1986). This in turn may
induce the synthesis of metallothionein within the tubular cells, or  the
free cadmium may bind directly to other tubular cell matter. As a
consequence of these events, urinary excretion is low, and cadmium has  a
strong tendency to accumulate in the body  (especially  in  the kidney)
over long periods of time.
     Because of the preferential accumulation of cadmium  in kidney, this
tissue is generally recognized to be the most sensitive to low-level
cadmium exposure. The chief effect  is  impairment of tubular reabsorption
of filtered solutes, including low-molecular-weight proteins,  minerals.
and metabolites, such as glucose or amino  acids. The effects  on mineral
retention (loss of calcium and phosphate)  are of greatest impact  on

-------
36   Section 4

health, sometimes resulting in painful bone resorption and kidney stone
formation. This process is compounded by an inhibitory effect of cadmium
on normal vitamin D formation in the kidney. It is generally accepted
that renal injury does not begin to become manifest in humans until the
concentration in the renal cortex exceeds -200
     Another effect of chronic cadmium exposure, which may be of general
health concern, is hypertension. While there is evidence for this effect
in animals, there is only limited evidence that cadmium is an important
risk factor in human hypertension. Similarly, there are data from animal
studies that show the immune system being affected by cadmium exposure ;
however, the health significance of this in humans is not known.

     Cadmium does not appear to be carcinogenic by the oral route.
However, inhalation exposure to cadmium has been found to increase the
incidence of lung tumors in animals and has been associated with an
increased frequency of lung tumors in occupationally exposed humans.

4.2  TOXICOKINETICS

4.2.1  Overview

     Cadmium ingested in food or water is absorbed with rather poor
efficiency (1 to 6%) from the gastrointestinal tract in both humans and
animals, depending considerably on the chemical form (especially the
solubility) and dose level of the cadmium, and on a number of parameters
of the exposed organism (age, sex, gastrointestinal contents, etc.). The
amount of inhaled cadmium absorbed through the lung depends on chemical
form and particle size (and hence, how deeply into the respiratory tree
the material penetrates), with most values ranging from 10 to 60%.

     Once cadmium is absorbed into the body, i£ is distributed to most
tissues, with strong preferential accumulation in kidney and liver.
Excretion, primarily in urine, is very slow (only a small percentage of
total body burden per day) , so there is a strong tendency for cadmium to
accumulate over time in exposed organisms. Estimated half -lives in
humans range from 17 to 38 years. The marked retention of cadmium in the
renal cortex underlies the characteristic renal injury that is the most
common toxicological consequence of chronic exposure.

4.2.2  Absorpt ion

4.2.2.1  Inhalation

     Cadmium compounds have low volatility and exist in air primarily as
suspensions of fine particulate matter. When inhaled, a fraction of this
particulate matter is deposited in the airway. Large particles  (e.g.,
10 jim) tend to be deposited in the upper airway, while small particles
(e.g., 0.1 /jm) tend to penetrate to the alveoli. While some soluble
cadmium compounds may undergo limited absorption in the upper
respiratory tree, the major site of absorption is the alveoli. Thus,
particle size (and hence alveolar deposition) is a key determinant of
cadmium absorption in the lung (Nordberg et al. 1985).

     Only limited data are available on the respiratory deposition of
cadmium compounds. In hamsters exposed to aerosols of CdCl2 with a mean

-------
                                                 Toxicological Data   37

size of 1.7 fim, about 19% of the dose was present in the lungs 2 h after
exposure (Henderson et al. 1979). Other estimates of alveolar deposiclon
in animals range from S to 20% (Banett et al. 1947, Boisset et al.
1978). No data on alveolar deposition in humans was found, but a
physiological model based on the characteristics of the human
respiratory tree suggests that only about 5% of large particles (10 *un)
will reach the alveoli, while up to 50% of small particles (0.1 pm) will
be deposited (Nordberg et al. 1985).
     Host available data suggest that cadmium compounds are relatively
well absorbed from the alveoli. For example, Hadley et al. (1980)
administered CdO to rats by instillation and recovered nearly 70% of the
dose in the liver and kidney within 2 weeks. Similarly, Boisset et al.
(1978) estimated that about 60% of the cadmium oxide deposited in the
lungs of rats was absorbed within 6 to 8 weeks. No direct measurements
of alveolar absorption in humans were found, but calculations based on
the increased body burden in smokers compared to that in nonsmokers
suggest that respiratory absorption in man is probably about 30 to 60%
(Friberg et al. 1974, Blinder et al. 1976).

A.2.2.2  Oral
     The fractional absorption of cadmium from the gastrointestinal
tract is usually relatively low, at least in adult organisms (Foulkes
1984). It is important to distinguish absorption from net retention of
an oral dose, since a portion of an oral dose may be trapped in the
intestinal mucosa without crossing into the blood or lymph (Foulkes
1986a).
     Several studies have measured cadmium retention in humans. HcLellan
et al. (1978) reported that in 14 healthy humans, an average of 5.9% of
an oral dose of CdCl2 was retained in the body at a time when a
simultaneously administered fecal marker (51Cr) had been completely
excreted. Shaikh and Smith (1980) reported a mean retention of 2.8% of
an oral dose of radioactive CdCl2 given to 12 subjects, with individual
values ranging from 1.1 to 7.0%.
     Estimates of oral absorption of cadmium in animals are slightly
lower than those in humans. Engstrom and Nordberg (1979) reported whole
body retention of 0.5 to 3.2% five days after exposure of mice to CdCl2,
and Moore et al. (1973) reported retention of 2.3% four days after oral
exposure of rats to CdCl2- Similarly, Friberg et al. (1974) reported
retention of 2.5 to 3.2% ten days after oral exposure of monkeys to
CdCl2.
     A number of factors are recognized which can influence the degree
of gastrointestinal absorption (Nordberg et al. 1985). Absorption
appears to be a saturable process; therefore, fractional absorption
tends to decrease at high dose levels (Foulkes 1980). The presence of
divalent and trivalent cations, such as Zn2+, Ca2+, Mg2+, Cr3*, and
others, decreases cadmium uptake, probably by a nonspecific effect on
the charge distribution on the intestinal brush border membrane  (Foulkes
1986a). Conversely, iron deficiency has been observed  to increase
dietary absorption of cadmium in both humans and animals  (Flanagan et
al. 1978).

-------
38   Section 4

     The effect of other dietary constituents is complex,  but absorption
from food (e.g., rat chow) is generally less than from milk,  which in
turn is less than from water (Foulkes 1986a).  A study in New Zealand
fishermen (Sharma et al.' 198-3) indicates that cadmium in oysters is
absorbed very poorly, with daily intakes of up to 300 jig/day causing
only small increases in blood and urinary cadmium levels.  Other
variables which affect absorption include age, with neonates absorbing
more than adults (Sasser and Jarboe 1977, Kostial et al. 1978), and sex,
with females absorbing more than males (Sumino et al. 1975).

4.2.2.3  Dermal

     Small quantities of cadmium may be absorbed through the skin
(Vahlberg 1965, Nordberg et al. 1985), but dermal absorption is not
normally a significant fraction of total cadmium absorption (Lauwerys
and Halcom 1985, Foulkes 1986a).

4.2.3  Distribution

     Table 4.1 lists mean tissue cadmium levels in human autopsy tissues
in Japan (Sumino et al. 1975). It is apparent that cadmium is widely
distributed in the body, with the major portion of the body burden
located in liver and renal cortex. Cadmium does not accumulate in bone,
and the blood-brain barrier appears to limit uptake into the central
nervous system. The development of neutron activation techniques (Harvey
et al.  1975) now permits the measurement of the tissue level of cadmium
in vivo, and several groups have confirmed that the highest levels of
cadmium are found in kidney. It should be noted that the tissue levels
shown in Table 4.1 are somewhat higher than typical for the United
States, since average cadmium body burdens in Japan are twofold to
threefold higher than those in the United States (Tsuchiya et al. 1972.
Friberg et al. 1974, Kowal et al. 1979).

     Many studies of cadmium levels in human autopsy samples have shown
that the average cadmium concentration in kidney tends to increase in a
roughly linear fashion as a function of age, beginning near zero at
birth and reaching a peak (typically around 40 to 50 pg/g) around age 50
(Friberg et al. 1974). After this age, renal concentrations tend to
plateau or begin to decline. Liver cadmium levels also begin near zero
at birth, then increase to values of around 1 to 2 pg/g by age 20 to 25
(Friberg et al. 1974, Chung et al. 1986). After this age,  levels in
liver tend to remain about constant or increase slightly (more so in
Japan than in the United States), and generally do not tend to decrease
after age 50 (Friberg et al. 1974, Chung et al. 1986). KJellstrom and
Nordberg (1985) have developed an eight-compartment kinetic model that
is useful in predicting the distribution of cadmium in body tissues as  a
function of dose and time.

     Distribution studies in animals show a pattern similar to that in
humans, with highest levels in kidney and liver and lower levels spread
throughout the rest of the body  (Friberg et al. 1985). Table 4.2 shows
the levels of cadmium measured in blood, liver, and kidney of rats
chronically exposed to various levels of cadmium in drinking water
(Bernard et al. 1980).

-------
                                       Toxicological Data    39
Table 4.1. Mean cadmium levels in human cadaver
                tissues in Japan
Tissue
Cerebrum
Cerebellum
Trachea
Lung
Heart
Liver
Pancreas
Spleen
Kidney*
Adrenals
Small intestine
Large intestine
Muscle
Skin
Blood
Bone
Testicles
Ovary
Mg/g wet weight (SD)
0.12
0.12
0.36
0.72
0.16
5.7
2.7
0.81
47
1.5
1.1
0.43
0.29
0.32
0.17
0.10
0.52
0.75
(0.06)
(0.06)
(0.22)
(0.52)
(-)
(4.6)
(1.7)
(0.69)
(24)
(1.0)
(0.4)
(0.22)
(0.24)
(0.28)
(0.11)
(0.06)
(0.24)
(0.51)
   "No indication was given whether whole kid-
ney or only cortex was analyzed.
   Source: Sumino et al. (1975).

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Section 4
             Table 4.2. Cadmium concentration in tissues of rats
                      exposed through drinking water
Concentration
in water
(mg/L)
0
2
20
200
Tissue concentration
Duration
(months)
11
11
11
8
Blood
(Mg/L)
1
5
35
180
Liver
(Mg/g)
0.3
3
20
260
Kidney
(Mg/g)
0.5
8
70
250
            Source: Bernard et al. (1980).

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                                                 Toxicol.ogj.cal Data   61

     Several studies suggest that the placenta is a partial barrier to
fetal exposure to cadmium. Lauwerys et al. (1978) reported that the
concentration of cadmium in the blood of a fetus is about 50% of that in
maternal blood, and Roels et al. (1978) found that levels of cadmium in
the placenta are about tenfold higher than those in maternal blood.
Similar findings were reported by Kuhnert et al. (1982). Christley and
Webster (1983) reported that only a small fraction (about 0.1%) of a
parenteral dose of cadmium administered to pregnant mice entered the
fetuses.
     Cadmium is present in.human milk, with reported concentrations
ranging from 10 to 100 ppb.  Schulte-Lobbert and Bonn (1977) studied the
concentration of cadmium in milk from five subjects and found that
concentrations were highest (22-35 ppb) in colostrum secreted on days
1 to 3 after birth, and that levels fell to around 10 ppb as mature milk
secretion began around day 4. Murthy and Rhea (1971) estimated that
infants may ingest about 0.01 mg/day cadmium from mother's milk, and
similar low-level exposure of nursing pups has been reported in rats by
Tanaka et al. (1972).

4.2.4  Metabolism
     Cadmium is not known to undergo any direct metabolic conversions in
vivo such as oxidation, reduction, or alkylation. The cadmium ion does
bind to protein and nonprotein sulfydryl groups (especially
glutathione), as well as to anionic groups in proteins and other
molecules.
     Of particular importance in the absorption, distribution, and
excretion of cadmium is its interaction with the protein metallothionein
(MT), which is a low-molecular-weight protein, very rich in cysteine,
and is capable of binding as many as 7 mol of cadmium per mol of
protein. MT has been detected in all tissues studied, including human
kidney, liver, heart, brain, skin, fibroblasts, muscle, and lung (CEC
1978). The complex chemical and biological properties of MT have been
frequently reviewed in detail (for example, see Goyer et al. 1984), and
the following points are most important: (1) most cells respond to
cadmium, zinc, and other metals by increased synthesis of MT;  (2) other
factors such as hormones and drugs can influence MT synthesis; and
(3) when present in plasma, the Cd-MT complex is readily diffusible and
filterable at the glomerulus and may be effectively reabsorbed from the
glomerular filtrate.
     The precise biological function of MT remains under discussion,
although a role in the storage and transport of beneficial metals  and/or
the detoxification of heavy metals seems likely  (Piscator  1964, Kagi and
Nordberg 1979, Petering and Fowler 1986). Whatever  its  evolutionary
function, increased levels of MT  increase intestinal trapping, decrease
intestinal absorption, and increase accumulation of cadmium  in MT-rich
tissues such as the liver and kidney  (Foulkes and McMullen 1986, Cherian
et al. 1978, Foulkes 1974).

-------
42   Section 4

4.2.5  Excretion

     The principal excretory route for cadmium is the urine. Average
daily excretion in humans is generally around 2 to 3 Mg/day, which
represents only a small fraction  (0.005 to 0.013%) of the body burden
(Tsuchiya et al. 1972, Friberg et al. 1974). Because excretion is so
slow, half-lives of cadmium in the body are correspondingly long (17 to
38 years), and cadmium accumulation over time is marked.
     Absolute levels of urinary cadmium increase when exposure levels
increase, but excretion rates remain a small fraction of total body
burden. If renal function (presumably the ability to reabsorb filtered
Cd-MT) becomes impaired, urinary excretion of cadmium may increase
sharply (Axelsson and Piscator 1966).

     Relatively high levels of cadmium (30 jig/day) are excreted in
feces, but this is almost entirely cadmium that was not absorbed from
the gastrointestinal tract (Tipton and Stewart 1970). However, Shaikh
and Lucis (1972) noted that as much as 5% of a parenteral dose of
cadmium may be excreted in the feces of rats within 4 days, mainly due
to biliary excretion (Klaassen 1978). Enteric secretion may also become
important when chelating agents are given for therapeutic purposes
(Kiyozumi and Kojima 1978).

4.3  TOXICITY
4.3.1  Lethality

     Inhalation exposure to high levels of cadmium oxide fumes is
intensely irritating to respiratory tissues. Typical symptoms, including
severe tracheobronchitis,  pneumonitis, and pulmonary edema, develop
within several hours (ACGIH 1986). These symptoms are unique to high-
dose inhalation exposure;  they do not resemble the effects of low-level
inhalation exposure or oral exposure. Concentrations that have produced
fatalities have been estimated to be 40 to 50 mg/m3 for 1 h (Blumer et
al. 1938, Barrett and Card 1947, ACGIH 1986), and 9 mg/m3 for 5 h (Beton
et al. 1966). Those surviving an acute episode may develop severe lung
changes several years later (Elinder 1986b). Similar acute effects are
observed in animals exposed to cadmium oxide fumes, with reported
inhalation LD50 values ranging from 500 to 15,000 (mg/m3)-min (Friberg
et al. 1974).

     Acute lethality from oral exposure of humans to cadmium is rare,
but doses of 1,500 to 8,900 mg (20 to 130 mgAg) have been reported to
cause death (CEC 1978). Acute oral lethality has been observed in a
number of animal studies,  and most LJ>50 values for cadmium oxide and
common cadmium salts range from 50 to 350 mgAg (CEC 1978).

4.3.2  Systemic/Target Organ Toxicity
4.3.2.1  Overview

     Exposure to cadmium is associated with injury to a number of
tissues or organs in both animals and humans, including the kidney,
liver, cardiovascular system, skeleton, and immune system. Similar
systemic effects are observed after inhalation and oral exposure but are
not observed following dermal exposure.

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                                                 Toxicological Data   43

     It is believed that occurrence of these effects depends on the
concentration of cadmium in  the respective target tissues. Because
cadmium is so highly retained  in the body, similar effects tend to occur
following shorter-term exposure to high doses or longer-term exposure to
low doses (Vang and Foulkes  1984). The concentration of cadmium in a
tissue at which adverse effects first begin to appear is termed the
tissue critical concentration, and the most sensitive tissue (that which
first attains a critical concentration following a specific type of
exposure) is termed the critical organ.  Under the low-level chronic
exposure conditions most often experienced by humans, the kidney is
generally recognized to be the critical organ, and most attention has
been paid to determining the critical concentration in kidney and the
exposures which will not exceed that concentration over a lifetime.
     Because individuals may differ in their sensitivity to cadmium, the
concept of critical concentrations has been expanded to apply to exposed
groups or populations (Kjellstrom et al. 1984). The population critical
concentrations (FCC) is the average concentration at which a specific
percentage of individuals display adverse effects in the tissue. For
example, the renal PCClQ is the average concentration of cadmium in the
kidney when 10% of the population is affected with cadmium-induced renal
dysfunction.

     While the concept of critical tissue concentrations has proved to
be a very useful means of describing and quantifying cadmium toxicity,
it is nevertheless somewhat simplistic, since the relationship between
tissue injury and tissue concentration depends on the form of cadmium in
the tissue (Raghaven and Gonick 1980; Nomiyama and Nomiyama 1982;
Foulkes 1986b, 1986c), which in turn depends on several toxicokinetic
and metabolic parameters. For instance, following acute injection of
cadmium-metallothionein in rats, Haitani et al. (1987) found the
critical concentration of cadmium in renal cortex was only 10 Mg/g, much
lower than the value observed after chronic oral or inhalation exposure
to cadmium.  When the same parenteral dose of cadmium-metallothionein was
divided and given over several days, levels of cadmium in kidney were
higher (30 pg/g) than after a single dose, but no renal damage was
observed.  The authors proposed that the cadmium ion released following
degradation of reabsorbed cadmium-metallothionein in renal tubular cells
resulted in increased synthesis of renal metallothionein, accounting for
the development of tolerance to subsequent cadmium exposure. Because the
apparent critical concentration depends on rate, route, and form of
exposure,  estimates of critical concentrations in one species or under
one set of exposure conditions may not be directly applicable to other
species or other exposure circumstances.

4.3.2.2  Renal effects

     As noted above, the renal cortex is the site of the highest cadmium
concentration reached in the body, either following chronic exposure or
after sufficient time has elapsed following acute exposure to permit
transfer of cadmium from other tissues, for example, from the liver to
the kidney.  The sensitivity of the kidney to cadmium was recognized by
Friberg (1950) during an investigation of workers exposed to cadmium
oxide dust in a factory producing nickel-cadmium batteries. These
workers suffered from a high incidence of abnormal renal function, which

-------
44   Section 4

was Indicated by proteinuria and a fall in the glomerular filtration
rate.  Subsequent studies revealed that this proteinuria is
characterized by the presence of a number of low-molecular-weight
proteins, including 02-nicroglobulin, lysozyme, ribonuclease,
immunoglobulin light chains, and retinol-binding protein (Piscator
1966). These proteins are all readily filtered at the glomerulus and are
normally reabsorbed in the proximal tubule; their excretion in urine is
therefore symptomatic of proximal tubular damage. Since decreased
reabsorption of these proteins (as measured by proteinuria) may
sometimes be obscured by a concomitant decrease in the glomerular
filtration rate, it is useful to normalize the urinary protein
concentration by dividing by the urinary creatinine levels.
     In chronic human exposure to cadmium, Kjellstrom et al. (1977b)
reported an average excretion of /92-microglobulin of 900 pg/g
creatinine, compared to a control value of only 75 >*g/g. Nogawa et al.
(1980) reported that over 90% of the males in a cadmium-polluted area in
Japan displayed microglobulinuria, and similar results were described by
Roels et al. (1981a) in a cadmium-polluted area in Belgium. Occurrence
of glomerular proteinuria (the urinary excretion of high-molecular-
weight proteins such as albumin as a result of glomerular damage) has
also been reported (Bernard et al. 1979), but its significance remains
under discussion (Elinder et al. 1985, Piscator 1986).

     The tubular proteinuria of cadmium intoxication may be accompanied
by depressed tubular reabsorption of other solutes such as enzymes,
amino acids, glucose, calcium, and inorganic phosphate. In some cases,
these other signs may be more sensitive for detecting tubular
dysfunction than proteinurea. For example, Nomiyama (1981) reported that
in the cadmium-exposed rabbit, enzymuria occurred when the cadmium level
in renal cortex reached 117 Mg/g, aminoaciduria was observed at about
200 Mg/g, but low-molecular-weight proteinuria only occurred at around
300 /ig/g.

     An increased frequency of renal stone formation has also been
reported in association with excess cadmium exposure (Scott et al.
1978). This is probably secondary to the effect of cadmium on mineral
and bone metabolism, as discussed further in Sect. 4.3.2.7.

     Tubular dysfunction usually appears only after relatively long
exposures, except when renal cadmium levels have been acutely elevated
(Gieske and Foulkes 1974). This time lag may represent the time required
for cadmium to reach a critical level in the renal cortex. As noted
above, the critical concentration of cadmium in a tissue depends on a
number of factors, but most studies indicate that a renal cortical
concentration of around 200 /ig/g wet weight is associated with an
increased incidence of renal dysfunction in at least some members of an
adult human population chronically exposed to cadmium (Friberg et al.
1974, Kjellstrom et al. 1977a, Roels et al. 1983, Kjellstrom et al.
1984, Kjellstrom 1986c). This value is based both on postmortem analysis
of tissue cadmium, and on the in vivo neutron activation analysis of
renal cadmium levels in patients with renal disease.

     Assuming a critical level of cadmium in renal cortex of 200 pg/g, a
fractional absorption of ingested cadmium of about 5%, and urinary
excretion of 0.01% of the body burden per day, Friberg et al. (1974)

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                                                 lexicological Data   45

calculated that daily oral intake of 352 jig/day over a period of
50 years would not exceed the critical level of cadmium in the renal
cortex.  More recently, Kjellstrom (1986a) reviewed a number of
epidemiological studies and concluded that average oral exposures of
about 200 /ig/day will cause tubular proteinuria in about 10% of an
exposed population by age 45. Using mathematical toxicokinetic models to
extrapolate to lower response rates, a dose of 50 Mg/day was estimated
to cause tubular proteinuria in about 1% of an exposed population after
45 years of exposure. By the inhalation route, Kjellstrom (1986a)
estimated that 10% of a worker population exposed to a concentration of
50 Mg/a3 would develop proteinuria in 10 years, and 1% would be affected
at an exposure level of 16 Mg/»3- Th* corresponding values for 50 years
of continuous exposure are about 2.2 and 0.7 jig/m3, respectively.
     Although the kidney is clearly a primary target organ of cadmium,
and although the renal functional lesions are not readily reversible
following cessation of exposure (Piscator 1984, Blinder et al. 1985),
chronic cadmium exposure seldom leads to end-stage renal disease or
increased mortality (Friberg et al. 1985). As pointed out by Piscator
(1986), the main problem associated with renal cadmium intoxication is
not the proteinuria per se, which seldom exceeds 2 g/day, but, rather,
is the effect on other tubular functions such as mineral reabsorption.

4.3.2.3  Hepatic effects
     Besides the kidney, the next highest tissue levels of cadmium are
found in liver, after both acute and chronic exposure (Kotsonis and
Klaassen 1977, 1978; Blinder 1986a). Following exposure to low doses of
cadmium, most of the cadmium in liver is bound to metallothionein, and
signs of liver injury are not observed (Colucci et al. 1975). Higher
doses result in saturation of HT-binding capacity, and cadmium binds to
other cell proteins causing injury. Dudley et al.  (1982) reported
extensive hepatic necrosis in rats exposed to cadmium by injection and
suggested that lethal effects of cadmium under such conditions may be at
least partly related to hepatic failure. Preexposure of animals  to
subtoxic doses of cadmium  (2 mg/kg  subcutaneously) results in increased
synthesis of metallothionein in the liver, which,  in turn, confers
protection against hepatic injury and death  from high doses  (5 mg/kg
intravenously) given one day later  (Goering  and Klaassen 1984).
     Chronic exposure also may cause hepatic changes in experimental
animals. For instance, Stowe et al. (1972) reported that livers  from
rabbits exposed to about 1.5 mmol CdCl2 in their drinking water  for  200
days (about: 13 pgAg/day) displayed many  structural changes,  although  a
series of clinical chemical  tests reflected  normal hepatic function.
Spom et al. (1970) observed changes  in carbohydrate and ATP metabolism
in the livers of rats chronically exposed to 25 ppm in  food,  and Miller
et al. (1974) described gross changes  in  the endoplasmic reticulum of
liver parenchymal cells from rats exposed to cadmium  in water (17  mg/L).

     There is little evidence for  liver dysfunction in  chronically
exposed human populations  (Bernard  and Lauwerys  1984, Blinder 1986a),
but hepatic levels may serve as  a useful  index of  exposure  and a
predictor of future  renal  dysfunction (Gompertz  et al.  1983, Kjellstrom
1986c). Roels et al.  (1981b) have  observed  that renal  dysfunction is

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46   Section 4

likely Co be present in workers whose liver levels of cadaiua exceed 30
to 60 ppm.

4.3.2.4  Cardiovascular effeccs
     In spice of extensive work, Che role, if any, of cadmium in human
cardiovascular disease remains uncertain. The field was recently
reviewed in greaC depth by Kopp (1986), who provided useful summaries of
Che controversial literature in this field.

     A number of studies, primarily in animals or isolated animal
tissues, indicate that Che function of both the heart and Che vascular
system may be impaired by cadmium exposure. Characteristic effects in
the heart include decreased speed and strength of contractions,  whereas
the effeccs in vascular smooch muscle may be either vasodilation or
vasoconstriction, depending on condicions. There is limited
epidemiological evidence that chronic cadmium exposure may cause
functional changes in Che heart or Che vasculacure of exposed humans;
however, Che daCa are inconclusive with respect Co Che ability of
cadmium Co cause significant cardiovascular pathology (Kopp 1986).

     Many of che effeccs of cadmium on Che cardiovascular syscem appear
Co be mediated by cadmium ancagonism of normal calcium ion fluxes in
cardiac and smooch muscles (Kopp 1986). Studies by Jamall and coworkers
indicate that cadmium may also affect che hearc Chrough a peroxidative
mechanism in which cadmium causes a decrease in che activity of
glutathione peroxidase and superoxide dismucase (Jamall and Smith 1985a,
1986).  HisCologlcal changes and evidence of peroxidacion are observed in
che hearc without concomicanc changes in che kidney (Jamall and Smich
1985b), even Chough Cissue levels of cadmium in Che hearc are lower Chan
in che kidney. The significance of chese observations Co human healch
risk is uncertain, since cadmium exposure is not generally observed to
cause increased incidence of cardiovascular disease.

     Another cardiovascular effect of concern is hypertension. Kopp et
al. (1978) reported that chronic exposure of rats to 0.044 mmol of
cadmium acetate in their drinking water (about 0.5 mg/kg/day) resulted
in small but significant increases in average systolic blood pressure
after 18 to 21 months of exposure. Other changes were also observed,
especially in the electrocardiogram. Similar results in animals have
been reported from other laboratories, but not all Investigators have
succeeded in confirming these findings. Kopp (1986) emphasized that the
conditions under which such studies have been conducted are important
determinants of the hypertensive response. Genetic and dietary factors
and route and rate of exposure are just some of the variables that may
influence the effects of cadmium. For example, the hypertensive response
in rats appears to be biphasic, reaching a maximum effect (an increase
of 12 to 14 mm Hg in average systolic pressure) at doses of around 0.1
mg/kg/day, but decreasing to normal or even below normal at exposure
levels of 5 to 10 mg/kg/day (Kopp 1986).

     The role of cadmium in human hypertension remains uncertain.
Schroeder (1965) observed a positive correlation between increased mean
renal cadmium concentration* In humans and the incidence of death from
hypertensive disease. Results supporting an association between cadmium
exposure and hypertension have been reported by other laboratories

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                                                 Toxlcologlcal Data   47

(e.g., Carrol 1966, Glauser et al. 1976, Nogawa et al. 1981a). However,
the incidence of hypertension is not increased in huaan populations
known to have been exposed to cadmium, as for instance in Japan
(Shigematsu et al. 1981) and Belgium (Staessen et al. 1984).  It appears
to be premature at this time, therefore, to conclude that cadmium is an
important etiological factor in human hypertensive disease,  especially
when judged in comparison to other determinants such as age,  body
weight, and diet.

4.3.2.5  Pulmonary effects

     Acute pulmonary exposure of humans or experimental animals to
cadmium in air may lead to marked bronchial and pulmonary irritation
(Elinder 1986b, Bernard and Lauwerys 1986), but these effects are very
unlikely to occur outside of the industrial environment.

     Of greater concern is impairment of lung function associated with
chronic inhalation exposure to low levels of cadmium. Friberg (1950)
reported that dyspnea was a common finding in workers chronically
exposed to cadmium, and one-third of the subjects displayed changes
indicative of emphysema. Similarly, Bonne11 (1955) observed emphysema in
workers chronically exposed to cadmium oxide, and Smith et al. (1976)
reported that the forced vital capacity in a group of workers exposed to
airborne cadmium was decreased in proportion to urinary cadmium
excretion. Some increased mortality from respiratory disease among
populations occupationally exposed to cadmium has been reported in
several surveys (Thun et al. 1985, Armstrong and Kazantzis 1985).
Emphysema has also been observed in rabbits exposed to cadmium (Friberg
1950), and fibrotic lesions have been observed in rats (Kutzman et al.
1986).

4.3.2.6  Gastrointestinal effects
     By the oral route, cadmium in high concentrations is a powerful
irritant of the gastrointestinal epithelium. Acute symptoms of oral
exposure include nausea, vomiting, salivation, abdominal pain, cramps,
and diarrhea (Bernard and Lauwerys 1984). The concentration of cadmium
in water that induces vomiting is about 15 mg/L (Lauwerys 1979), and a
dose of 3 mg is considered to be the emetic threshold (CEC 1978).
Chronic oral exposure to cadmium has also been suspected of causing a
gastrointestinal malabsorption syndrome referred to by Murata et al.
(1970) as cadmium enteropathy.

4.3.2.7  Skeletal effects
     Painful bone disorders, including osteomalacia, osteoporosis, and
spontaneous bone fracture, have been observed in some humans chronically
exposed to high levels of cadmium. These symptoms have been most
thoroughly studied in postmenopausal women living in a cadmium*
contaminated area in Japan, where the affliction is called Itai-Itai
disease (Hagino and Yoshioka 1961). Osteomalacia has also been observed
in some occupationally exposed workers  (Scott et al. 1980, Nicaud  et  al.
1942). These effects on bone are generally considered to be  indirect,
arising as a consequence of cadmium-induced renal disease (e.g.,
calcuria and phosphaturia), compounded by  an  inhibition of normal

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48   Section 4

1-hydroxylation of 25-hydroxy-vitamin 03 in renal tubule cells
(Kjellstrom 1986b, Nomiyama 1986, Nogawa et al.  1987).

     Studies in animals also indicate that cadmium exposure may affect
the skeleton. Nogawa et al. (1981) exposed rats  to CdCl2 for 2 years and
observed that cadmium led to decreased calcium content  in bone
accompanied by marked renal tubular injury and increased urinary
excretion of calcium. Similar findings were reported by Kawamura et al.
(1978). Other workers have reported that the effects of cadmium on bone
in animals is markedly increased by dietary calcium deficiency (Larsson
and Piscator 1971, Itokawa et al. 1974).
     Some workers have questioned the role of cadmium in Itai-Itai
disease, since skeletal lesions are not common even in  heavily exposed
persons, and since the disease does occur in some people who have not
been heavily exposed. Because of these observations, some researchers
consider it likely that nutritional deficiency plays an important role
in the etiology of Itai-Itai disease, and that cadmium  exposure may
enhance the incidence or severity of the disease through its effects on
the kidney (Kato et al. 1978, CEC 1978, Kjellstrom 1986b).

4.3.2.8  Effects on the immune system
     Effects of cadmium on the immune system have been studied
extensively over the last 10 years and have recently been reviewed in
some detail by Exon and Koller (1986). While many of the findings are
contradictory, there is little question that relatively low doses of
cadmium can alter the immune response in experimental animals. For
example, Koller et al. (1975) observed decreased levels of spleen
plaque-forming cells in mice exposed to 0.6 mg/kg/day for 10 weeks. More
recently, Blakley (1985) reported a dose-dependent suppression of the
humoral immune response in mice exposed for 3 weeks to 5 to 50 mg/L
cadmium in drinking water. These functional alterations in the immune
system were associated with very low renal cadmium concentrations (0.3
to 6.0 Mg/g). which is considerably lover than the suggested critical
level of cadmium in renal cortex in chronically exposed humans. The mice
appeared to tolerate the cadmium exposure without difficulty; whether
the effects on the immune system are clinically significant is not
known. At present, there Is little evidence for suppression of the
immune response in chronically exposed human populations.

4.3.2.9  Effects on testes, ovaries, and placenta

     Parenteral injection of cadmium has been observed to cause severe
acute pathological changes in the gonads in animals, especially in
males. For example, Parlzek  (1957) reported that  injection of male rats
with 2.2 mgAg of CdCl2 causes an Initial swelling and inflammation of
the testes, followed by necrosis and atrophy. Similar results have been
observed by others (CEC 1978, Laskey et al. 1984), and cadmium injection
has even been investigated as a male sterilization procedure. Very large
oral doses (100 mgAg or higher) have also been reported  to cause acute
testicular damage similar  to that following injection  (Kotsonis and
Klaassen 1977).

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                                                 Toxicological Data   49

     Cadmium-Induced testicular damage appears to be mediated in large
part by an effect on the testicular vascular bed. Shortly after
parenteral exposure there is a sharp increase in permeability of the
capillaries, and this in turn leads to interstitial edema, decreased
capillary blood flow, ischemia, and, ultimately, tissue necrosis (Aoki
and Hoffer 1978). The basis for the tissue-specific nature of this
effect is not known, but the problem is likely related to cadmium
inhibition of one or more testes-specific enzymes, isozymes, or binding
proteins (Hodgen et al. 1970, Chen et al. 1974, Omaye and Tappel 1975).

     Degenerative effects in testes are not usually observed in
chronic-exposure studies in animals, perhaps as a result of
metallothionein induction (Kotsonis and Klaassen 1978). For example,
Piscator and Axelsson (1970) administered repeated subcutaneous
injections of 0.25 mg/kg cadmium to rabbits for up to 24 weeks,
observing no histological evidence of testicular damage, in spite of the
fact that this treatment did cause renal injury. Similarly, Loeser and
Lorke (1977a,  1977b) found no significant histological damage in testes
of dogs or rats fed up to 30 ppm in the diet for 3 months, corresponding
to doses of about 0.75 to 1.5 mg/kg/day, respectively. Testicular damage
has not been reported in occupationally exposed humans, even when
testicular levels of cadmium are elevated (Smith et al. 1960).

     The ovaries and the placenta are also affected by large parenteral
doses of cadmium, although the effects are usually less severe than
those suffered by males in their reproductive organs. Parizek et al.
(1968) observed massive ovarian hemorrhage in rats given subcutaneous
injections of 2.3 to 4.6 mg/kg cadmium, and similar effects were
observed in mice by Uatanabe et al. (1977). Parizek (1964) described a
progression of hemorrhage and necrosis in the placenta of rats following
subcutaneous injection of 4.5 mg/kg cadmium on days 17 to 21 of
gestation. Parizek (1964) hypothesized that the injury to ovary and
placenta, and possibly to testes as well, was due to destruction of
estrogen secretion by the endocrine cells of these tissues, with
resultant failure of normal capillary blood flow.

4.3.2.10  Other systemic effects
     In addition to the various systems discussed above, a variety of
other tissues may show altered function as a result of cadmium exposure.
     A common but not universal finding in cadmium-exposed animals is
anemia. Bone marrow hypoplasia was produced in mice by long-term oral
cadmium administration (Wilson et al. 1941), and exposure during
gestation has been noted to cause maternal and/or fetal anemia in rats
(Webster 1978, Kelman et al. 1978, Prigge 1978). Somewhat lowered
hemoglobin concentrations and decreased packed cell volumes have been
observed in cadmium-exposed workers, and it was suggested that cadmium
interferes with iron absorption from the intestine (Berlin and Friberg
1960). Halabsorption of iron and various other solutes following cadmium
exposure has been suspected by several investigators, and Hurata et al.
(1970) coined the concept of cadmium enteropathy to describe  this
condition. Reduced gastrointestinal absorption of vitamin D,  calcium,
and phosphate could contribute to the osteomalacia of Itai-Itai disease.

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 50   Section 4

     While  parenteral  adninistraelon of high doses of cadmium can cause
 lesions  in  the nervous system of experimental animals, evidence  for
 neurologic  effects  following long-term oral or inhalation exposure of
 animals  or  man is limited.  Oral  cadmium administration in the rat
 increased passive avoidance behavior (Nation et al. 1984), and
 neurobehavioral  changes have been observed in rats following exposure to
 cadmium  in  utero (Baranski  1986,  1987). Wong and Klaassen (1982) found
 that newborn rats were relatively more sensitive to the neurotoxic
 effects  of  injected cadmium than adults. A 4.0 mg/kg dose of cadmium
 caused lesions in the  corpus callosum, caudate putamen, and cerebellum
 when injected into  4-day-old rats, but the same dose did not produce any
 morphological changes  in  adult rats.  The authors suggested that  the
 sensitivity of the  newborn  rats  might result from an immature blood-
 brain barrier.

 4.3.3  Developmental Toxicity

     Many studies report  developmental or teratogenic effects in animals
 following intravenous  or  subcutaneous injection of high doses of cadmium
 salts (EPA  1981, CEC 1978).  For  example, Ishizu et al. (1973)
 administered CdCl2  to  mice  by subcutaneous injection on day 7 of
 pregnancy and found teratogenicity and increased fetal mortality at
 doses of 0.63 mg/kg or higher. A dose of 0.33 mg/kg did not have any
 effect on the offspring.  Similar findings were observed in hamsters,
 with marked malformations of the face, limbs, and skeleton following
 intravenous injection  with  2 mg/kg on days 8 or 9 of gestation (Fern and
 Carpenter 1967,  Ferm 1971,  Gale  and  Fern 1973).

     The teratogenic and  fetotoxic effects of cadmium are dependent on
 the zinc status  of  the animal, being increased by zinc deficiency (Sato
 et al. 1985) and decreased  by zinc supplementation (Ferm and Carpenter
 1968). These findings  suggest that the developmental toxicity of cadmium
 may be mediated  by  inhibition of some key zinc enzyme.

     When exposure  is  by  ingestion.  the most common finding is decreased
 weight of offspring, usually without significant teratogenic or
 developmental effects.  For  example,  Pond and Walker (1975) exposed rats
 to 200 ppm  CdCl2 in the diet (about  15 mg/kg/day) and observed a
 decrease in pup  weight but  no evidence of teratogenicity or
 embryolethality. Similarly.  Sutou et al. (1980) reported no teratogenic
 or developmental effects  (except for delayed ossification) in fetuses
 from dams dosed by  gavage with doses up to 10 mg/kg/day for 6 weeks
 prior to and during breeding and gestation. Prigge (1978) exposed rats
 to airborne cadmium at concentrations of 0.2 to 0.6 mg/m3 during
 gestation.  The researcher observed a reduction in both maternal  and
 fetal weight gain but  no  significant teratogenicity. Likewise, Cvetkova
.(1970), as  cited in Frlberg et al. (1974), reported decreased pup weight
 and elevated perinatal mortality in  rats exposed to cadmium by
 inhalation  (3 mg/m3),  but no teratogenic or developmental effects were
 noted. Cvetkova  (1970)  also reported decreased birth weights in  pregnant
 women exposed to airborne cadmium under occupational conditions, but no
 congenital malformations were observed.

     However, some  investigators have reported developmental effects
 following cadmium exposure.  Schroeder and Hitchner (1971) described a

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                                                 Toxicologies! Data   51

congenital tail malformation  in  a  three-generation study of rats exposed
to 10 mg/L of CdCl2  in drinking  water  (about 1 mg/kg/day), and Baranski
(1985) reported sirenomelia (fused legs)  in offspring of rats dosed by
gavage with CdCl2  (40 mg/kg)  on  days 7  to 16 of gestation. Evidence of
impaired neurobehavioral development in rats (as judged by decreased
neonatal exploratory activity and  delayed avoidance acquisition) has
been reported following exposure of dams  by gavage (0.4 or 4.0 mg/kg,
given for 5 weeks  preceding and  continuing through gestation),  drinking
water (60 mg/L given during gestation), or inhalation (0.02 or
0.16 mg/m3, 5 h/day, 5 days/week for 5 months preceeding and then
continuing through gestation) (Baranski et al. 1983; Baranski 1984,
1986, 1987). Whether these effects  are reversible or biologically
significant is not known.

     Cadmium exposure has not been  observed to cause teratogenic or
other developmental  effects in exposed humans (CEC 1978, Bernard and
Lauwerys 1984).

4.3.4  Reproductive  Toxicity

     As described  above, high parenteral  doses of cadmium administered
to experimental animals may cause severe  injury to the gonads,
especially in males, and this frequently  results in reduced fertility or
complete sterility.  Laskey et al.  (1984)  found severely depressed
testosterone levels  and no viable sperm in male rats injected with doses
of 1.8 mg/kg of CdCl2 14 days previously.  Similarly, Saksena et al.
(1977) observed a  marked reduction  in sperm count of male rats injected
with 1 mg/kg of CdCl2 15 days previously,  although no decrease in
fertility was observed until  the dose reached 5 mg/kg.

     In contrast to  these dramatic  effects following large parenteral
doses of cadmium,  most studies involving  oral exposure do not reveal
significant effects  on reproductive function. Dixon et al. (1976) found
no effects on sperm  morphology or reproductive success in male rats
given single oral  doses up to 25 mg/kg of CdCl2. Kotsonis and Klaassen
(1977) reported similar findings in rats  given single oral doses up to
50 mg/kg of CdCl2, but they did  observe some testicular damage and
impaired fertility in males given single  oral doses of 100 or 150 mgAg-
Zenick et al. (1982) supplied male  rats with water containing up to
68.8 mg/L cadmium  (about 7 mg/kg/day) for 70 days, observing no effects
on sperm count, sperm morphology, or reproductive success.

     Likewise, oral  exposure  of  female animals to cadmium is rarely
observed to affect reproductive  function,  except at doses which produce
frank maternal toxicity. Baranski et al.  (1983) administered CdCl2 by
gavage to female rats at doses of 0.04, 0.4, or 4.0 mg/kg/day for
5 weeks preceeding and then continuing during mating and gestation.
These doses did not  affect maternal survival, and no effects on
fertility were detected. Sutou et al.  (1980) exposed male and female
rats to doses of 0.1, 1.0, or 10 mg/kg/day by gavage for 6 weeks, and
they found no significant effects on five indices of fertility, although
the number of live fetuses per dam  was decreased in the high-dose group.

     However, a few  studies have reported reproductive effects following
chronic oral cadmium exposure. Schroeder  and Mitchner (1971) reported
breeding failure in  the F2 generation of  rats supplied with water

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52   Section 4

containing 10 mg/L of CdCl2-  In addition, Wills et al. (1981) reported a
progressive decrease in the number of litters per dam in a
four-generation study in rats fed 100 to 125 ppm of cadmium in the diet
(about  5 to 10 mg/kg/day). This was judged to be due to a failure of
fertilization rather than an  effect of cadmium on embryos or fetuses.

     Reproductive effects of  cadmium have not been reported in humans.
4.3.5   Genotoxicity
4.3.5.1 Gene mutation studies

     Cadmium compounds have been tested for mutagenic activity in a
number  of assay systems. Studies in Salmonella eyphiaurluia (Meddle and
Bruce 1977, MiIvy and Kay 1978, Polukhina et al. 1977, Hedenstedt et al.
1979, Mandel and Ryser 1981), E. coll (Venitt and Levy 1974), and yeast
(Takahashi 1972, Putrament et al. 1977) have produced inconclusive
results. Recombination assays in Bacillus subtLlls have yielded weak
positive responses (Nishioka  1975, Kanematsu et al. 1980). The available
data suggest that cadmium is mutagenic in mammalian cell culture assay
systems. Cadmium has been demonstrated to be mutagenic both in the mouse
lymphoma assay (Amacher and Palllet 1980, Oberly et al.  1982) and in the
Chinese hamster cell assay (Castro 1976).

4.3.5.2  Chromosomal aberration studies

     Conflicting results have been reported for chromosomal aberration
studies in human lymphocytes from exposed workers and in human and
animal  cell lines treated with cadmium in vitro. In Chinese hamster
cells,  chromosomal aberrations were reported following treatment with
1CT8 to 10'5 mol cadmium sulfate (Rohr and Bauchinger 1976) or
2 x 10'6 mol cadmium chloride (Deaven and Campbell 1980). In human
lymphocytes exposed to cadmium chloride in vitro, negative results were
observed by Dekundt and Deminatti (1978), Paton and Allison (1972), and
O'Riordan et al. (1978), whereas exposure to cadmium acetate and cadmium
sulfide has produced positive results (Shiraishi et al.  1972, Gasiorek
and Bauchinger 1981). Examination of lymphocytes taken from humans with
above-average cadmium exposure has produced both positive responses
(Bauchinger et al. 1976) and negative responses (Dekundt et al.  1973,
O'Riordan et al. 1978,  Shiraishi and Yoshida 1972. Bui et al. 1975).
Negative in vivo results have also been reported in mouse bone marrow
(Dekundt and Gerber 1979), in a mouse micronucleus assay (Heddle and
Bruce 1977), and in dominant lethal assays (Epstein et al. 1972,
Gilliavod and Lenard 1975, Suter 1975).

4.3.6   Care inogenicity

4.3.6.1  Inhalation

     Human.  The relationship between inhalation exposure to cadmium and
increased risk of cancer (particularly lung cancer and prostatic cancer)
has been explored in a number of epidemiological studies. The data are
sometimes conflicting and are often limited by confounding factors such
as smoking and exposure to other chemicals.

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                                                  Toxlcologlcal  Data    S3

      Kipling and Vaterhouse (1967) reported a statistically significant
 Increase  In prostate cancer In a study of 246 workers  exposed to cadmium
 oxide dust for a minimum of 1 year.  No significant differences  were
 reported  between the observed and expected number of cancers of the
 bronchus,  bladder,  or testls or for all combined sites. While these
 results are statistically significant,  they provide only  limited
 evidence  that cadmium is a human carcinogen.  The investigators  did not
 allow for a sufficient latency period in the exposed workers and did not
 adequately describe the derivation of expected deaths.

      Holden (1980)  conducted a cohort mortality study  with  British
 cadmium workers,  with iron and brass  foundry workers in a second factory
 serving as a control.  The cadmium factory was divided  Into  two  sections,
 a cadmium alloy department (estimated mean cadmium level  of 70  pg/m3)
 and  the remaining part of the factory (estimated mean  cadmium level of 6
 pg/m3). There was a statistically significant elevated risk of  dying
 from all  causes in  the cadmium copper alloy workers. Mortality  from
 neoplasms  was not significantly increased in these workers  except for
 deaths due to leukemia.  A statistically significant elevated risk of
 cancer was observed in workers In the remaining part of the cadmium
 factory due to an excess risk of lung and prostate cancer.  Holden
 attributed the elevated risk of lung  cancer to exposure to  other metals.
 Including  arsenic.

      Sorahan and  Vaterhouse  (1983) performed an historic  prospective
 mortality  study of  nickel-cadmium battery workers.  They found the
 incidence  of respiratory cancer to be increased among  workers moderately
 or highly  exposed to cadmium oxide dust and Initially  employed before
 1940. However,  this finding  was confounded by exposures to  oxyacetylene
 welding fumes and to nickel  hydroxide dust.  They also  reported  an
 Increase  in prostate cancer,  but the  difference in incidence compared to
 the controls  was  not significant.

      In a  follow-up study of workers  in this  factory,  Sorahan (1987)
 found no evidence of an association between risk of lung  cancer and
 duration of employment in Jobs with high or moderate levels of cadmium
 exposure.   On this basis,  Sorahan concluded that inhalation  exposure to
 cadmium oxide dust  does  not  increase  risk of  lung cancer.

      Blinder  et al.  (1985) studied workers  who had been exposed to
 cadmium for at lease one year between 1940 and 1980 in a  Swedish
 cadmium-nickel battery factory.  Levels  of cadmium oxide dust in air had
been  about 1  mg/a3  before 1947,  0.3 mg/m3  in  1947  to 1962, 0.05 mg/m3 in
 1962  to 1974,  and 0.02 mg/m3 since 1975.  The  standard  mortality ratio
 (SMR) for  both prostatic cancer and lung cancer tended to increase with
 estimated  dose and  duration  of exposure but did not reach statistical
 significance.  The authors concluded that long-term high-level exposure
 to cadaiua la  likely associated with  increased risk of lung cancer.

      Lemen et  al. (1976)  conducted an historical prospective study on
292 white  aale smelter workers exposed  to  cadmium for  a minimum of 2
years. The  average  exposure  level was about 1.5 «g/m3, with an upper-
bound estimate of exposure of 6 mg/m3.  A statistically significant
association between exposure to cadmium and an Increased  incidence of
prostatic  carcinomas,  bronchogenic carcinomas,  and total  malignant
neoplasms was  observed.  Smoking histories  for members  of  the cohort were

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54   Section 4

not available. Mentor* of the cohort were also exposed to other metals,
including arsenic, lead, and zinc.

     A follow-up retrospective mortality study at this sane cadmium-
processing plant was performed by Thun et al. (1985). This study
included 602 white males employed for a minimum of 6 months between 1940
and 1969. Estimated 24-h average exposure levels ranged from 170 to
2,500 jig/m3. Based on estimates of cumulative exposure, members of the
study population were divided into three groups: <585, 585 to 2,920, and
>2,920 (mg/m3)-days. These exposures were calculated to be equivalent to
40-year time-weighted average concentrations of <40, 40 to 200, or >200
Mg/»- The standardized mortality ratios for lung cancer in these groups
were 53, 152, and 280, respectively. Although the excess mortality was
statistically significant only for the high-exposure group [>2,920
(mg/m3)-days], the dose-response trend across all groups was highly
significant (? - 0.001).

     A confounding factor of concern in the Thun study is the possible
role of arsenic in the observed excess lung cancer mortality. The
cadmium plant under study had previously been an arsenic smelter, and
arsenic was also an impurity in the feedstock used to produce cadmium.
Based on estimates of likely worker exposure to airborne arsenic. Thun
et al. (1985) concluded that arsenic could not explain the excess
mortality. This conclusion is disputed by White (1985) and Lamm (1987),
who have analyzed the same data and concluded that the probable cause of
excess lung cancer is arsenic and not cadmium.

     Armstrong and Kazantzis (1983) studied the mortality of nearly
7,000 men who had been exposed to cadmium for more than one year in 19
different plants in England. Ho excess deaths were observed for
prostatic cancer. There were marginally more deaths from lung cancer
than expected, but this excess was not related to exposure levels. In a
more detailed study of a cohort of 4,393 men employed at a zinc-lead-
cadmium smelter, Ades and Kazantzis (1988) observed statistically
significant lung cancer excess (SMR - 124.5), with a trend toward
increased incidence as a function of employment duration. However, as in
the earlier study, this risk did not correlate vith estimated cumulative
cadmium exposure levels, and the authors concluded that cadmium was not
responsible for the observed excess lung cancer.

     Other investigations have provided suggestive evidence of an
association between cadmium and prostate cancer (McMichael et al.
1976a,b; Plscator 1981; Andersson et al. 1982; Kjellstrom 1982) and
between cadmium and renal cancer (Kolonel 1976). Whereas several studies
have not detected a correlation between excess cancer mortality and
exposure to cadmium (Humperdink 1968, Potts 1965, Monaon and Fine 1978.
Kjellstrom et al. 1979, Goldsmith et al. 1980, Inakip and Beral 1982),
these studies vere limited by lev statistical power, other risk factors,
or poor exposure information (EPA 1985b).

     Animal.  Chronic inhalation exposure of rats to cadmium chloride
aerosols has been shown to produce significant increases in lung tumors.
Takenaka et al. (1983) exposed groups of male rats continuously to
cadmium chloride by inhalation for 18 months, followed by a 13-month
observation period. Exposure concentrations were 0, 12.5, 25. or
50 pg/m3, corresponding to lifetime average doses of 0, 6.0, 11.4, or

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                                                 lexicological Data   55

22.8 pg/kg/day- There were no treataent-related differences in mean body
weights or in mean survival times between treated and control rats. A
dose-related increase in primary lung carcinomas was observed, with
incidences of 0, 15.4, 52.6, and 71.4%, respectively. The carcinomas
observed were primarily adenocarcinomas, with smaller numbers of
epidermoid, mucoepidermoid, and combined-type carcinomas. The first
epidermoid carcinoma and the first adenocarcinoma were found at 20 and
22 months, respectively. Metastases to the regional lymph nodes and the
kidneys and invasion into the regional lymph nodes and the heart
occurred in some animals with lung tumors.
     The positive results of the study by Takenaka et al. (1983) are
supported by two experiments that utilized intratracheal instillation.
Sanders and Hahaffey (1984) reported that intratracheal instillation of
cadmium oxide (1, 2, or 3 doses of 25 pg) produced an increase in
mammary tumors and an increase in tumors at multiple sites in male
Fischer rats, although no increase in lung tumors was observed. Hoffmann
et al. (1985) reported intratracheal instillation of single doses of
cadmium chloride produced invasive prostatic carcinomas in 5 out of 100
rats 270 days after treatment.

4.3.6.2  Oral
     Human.  There are presently no data to suggest that oral exposure
of humans to cadmium is associated with increased risk of cancer (EPA
1984, Bernard and Lauwerys 1986). Mortality studies in areas of Japan
and Europe, where oral cadmium exposure is elevated, have not revealed
any observable increase in mortality from cancer, including prostatic
cancer (Shigematsu et al. 1981. Nogawa et al. 1981a, Lauwerys and DeWals
1981, Elinder and KJellstrom 1986).
     Animal.  Studies conducted to date in animals have not shown
cadmium to be carcinogenic by the oral route. Schroeder et al.  (1964)
reported that 5 ppm cadmium acetate given in drinking water to  Swiss
mice (about 1 mg/kg/day) was not carcinogenic. However, this study was
limited due to reduced survival of the treated animals and a high  tumor
mortality rate in the control group. In a second lifetime study by
Schroeder et al. (1965). no significant increases in the incidence of
tumors were observed in Long-Evans rats given drinking water containing
5 ppm cadmium acetate (about 0.5 mg/kg/<*ay) • Malcolm, (1972) reported
negative findings in Chester-Beatty rats given up to 0.8 mg of  cadmium
sulfate by gavage weekly for 2 years (an average dose of about
0.4 mgAg/day)- No difference in tumor  incidence was observed between
male Chester-Beatty rats given 0.087, 0.18, or 0.35 mgAg of  cadmium
sulfate by gavage once weekly for 2 years and controls receiving 1 mL of
distilled water on the same regimen (Levy and Clark  1975). Similarly,
Levy et al. (1975) reported negative results for groups  of male Swiss
mice given cadmium sulfate at doses of  0.44, 0.88, or 1.75 mg/kg/veek by
gavage for 18 months. In both of these  studies,  the histopathological
examination was limited compared to contemporary standards.  In a study
conducted by the Food and  Drug Administration  (FDA 1977). groups of
Charles River caesarean-originated, barrier-sustained  (COBS)  Sprague-
Dawley (SD) rats were fed  diets containing  0, 0.6, 6, 30, 60,  or 90 ppm
cadmium for 103 weeks. No  significant  differences  in the tumor
incidences of  the control  and  treated  groups were  reported.  Looser

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56   Section 4

(1980) also conducted a 2-year feeding study with Vistar rats. There
were no significant differences in the incidence of tumors in Vistar
rats fed diets containing 0, 1, 3, 10, or 50 ppm of cadmium chloride.

4.3.6.3  Dermal

     There is no evidence that dermal exposure is carcinogenic in either
animals or humans.

4.4  INTERACTIONS WITH OTHER CHEMICALS

     A number of reports reveal that the toxicity of cadmium is
influenced by the dietary and trace metal status of the exposed
organism. In general, dietary deficiencies of metals (including zinc,
iron, copper, selenium, and calcium) increase the toxicity of cadmium,
and, conversely, increased dietary intake of these metals appears to
have a protective effect against cadmium toxicity. In animals, zinc has
been reported to reduce or prevent cadmium-induced growth inhibition,
tumor induction, testicular damage, and teratogenic effects (Parizek
1957; Parizek et al. 1969; Perm and Carpenter 1967; Gunn et al. 1963a,b,
1964). Copper has also been reported to reduce or prevent mortality,
anemia, and aortic elastin degeneration (Hill et al. 1963, Bunn and
Matrone 1966) , whereas selenium has been shown to prevent testicular
damage and hepatic changes and decrease lethality in rodents (Parizek et
al. 1969, Gunn et al. 1968). Experiments with Japanese quail
demonstrated that single or combined deficiencies of zinc, copper, iron,
calcium,  and protein intensify the toxic effects of cadmium (Fox et al.
1979). Miller et al. (1974) showed that deficiencies of copper and zinc
increased proliferation of hepatic endoplasmic reticulum in rats exposed
to cadmium in drinking water. It has also been shown that elevated
cadmium intake interferes with calcium metabolism (Foulkes 1986a).

     Possible mechanisms for these interactions include changes in
intestinal absorption of cadmium in the presence of trace metals,
metallothionein induction, and competition among metal ions for enzyme
or regulatory protein binding sites.

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                                                                       57
                5.   HANUFACTDRE,  IMPORT.  USE.  AND DISPOSAL

 5.1  OVERVIEW

      Approximately 1,010 metric  tons (Mg)  of  cadmium was  produced  in  the
 United States in 1982.  Major uses include  metal  plating,  pigments,
 batteries,  and plastic  stabilizers,  that together accounted  for  92%
 (4,400 Mg)  of the  cadmium used in the United  States  in  1981. While air
 and water emissions of  cadmium may be substantial, most cadmium  used  in
 the United  States  is disposed of on  land.

 5.2  PRODUCTION

      Cadmium  is produced as  a by-product during  the  processing of
 zinc-bearing  ores  (e.g.,  sphalerite),  and  also from  smelting of  lead  and
 copper ores (e.g.,  galena and malachite)  (HSDB 1987,  EPA  1985a). Cadmium
 oxide  produced during roasting is reduced  with coke,  and  the metal is
 separated by  distillation or electrodeposition.  Major producers  of
 cadmium include AMAX, Inc.  (Sauget,  Illinois); ASARCO,  Inc.  (Denver,
 Colorado); Zinc Corporation  of America (Bartlesville, Oklahoma); and
 Jersey Miniere Zinc Co.  (Clarksville,  Tennessee)  (DOI 1987). Total
 cadmium production  in the United States  was 2,000 Mg in 1977, 1,010 Mg
 in  1982, and  1,600  Mg in 1985 (DOI 1987, HSDB 1987).

 5.3  IMPORT

     From the  1950s to  the mid 1970s,  the  United States imported only
 about  10 to 20%  of  the  cadmium consumed  annually. Following the  abrupt
 increase in the  cost  of oil  in 1973  to 1974, imports  have accounted for
 about  60% of annual consumption,  typically around 2,000 Mg/year  (DOI
 1987,  HSDB 1987). Until 1970,  exports  were usually about equal to
 imports, but exports  are  now small (86 Mg  in 1985) (DOI 1987).

 5.4  USE

     Between 1978 and 1982,  total domestic usage  of  cadmium fluctuated
between 3,500  and 5,100 Mg.  Of the total 3,720 Mg used  in 1985,  35% was
 for metal plating,  20%  for pigments,  25% for nickel-cadmium and  other
batteries,  15%  for  plastic stabilizers, and 5% for other uses, including
pesticides,  alloys, and chemical  reagents  and/or  intermediates (DOI
1987).

5.5  DISPOSAL

     Estimates of the amount  of cadmium disposal  resulting from
production and use vary considerably.  However, it is  clear that  while
substantial quantities of cadmium may  be discharged  to water
(570 Mg/year)  or emitted  to  air  (890 Mg/year) during  production  and/or

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58   Section 51
use processes, most of the cadmium used in the United States (typically
about 3,500 Mg/year) is land disposed. Municipal waste disposal of
cadmium-containing products to landfills accounts for a major proportion
of cadmium disposal (EPA 1985a).  If the refuse in municipal waste sites
is incinerated, cadmium in nickel•cadmium batteries and other cadmium-
containing products may be released into air with fly ash.

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                                                                      59
                         6.  ENVIRONMENTAL FATE

6.1  OVERVIEW
     Cadmium enters the environment to a limited extent from the natural
weathering of minerals, but to a much greater degree from pollutant
sources such as discarded metal-containing products, phosphate
fertilizer, and fuel combustion.
     Atmospheric cadmium is in the form of particulate matter, which may
consist of very small particles if it is produced by combustion of fuel
containing cadmium. The principal chemical species is cadmium oxide,
although some cadmium salts may also occur. These are stable compounds
that do not undergo significant chemical transformations. The chief fate
of airborne cadmium is dispersion by wind and either wet- or dry-surf ace
deposition.
     In surface water and groundwater, cadmium can exist as the hydrated
ion or as ionic complexes with other Inorganic or organic material.
Although the soluble forms may migrate, insoluble complexes or cadmium
adsorbed to sediments are relatively nonmobile. Similarly, cadmium in
soil may exist in soluble form in soil water, or in insoluble complexes
with inorganic and organic soil substituents. Cadmium is taken up and
retained by plants (both aquatic and terrestrial). Animals (including
humans) can then be exposed by ingesting plants or the flesh of other
animals that consume the plants.

6.2  RELEASES TO THE ENVIRONMENT

6.2.1  Anthropogenic
     Significant quantities of cadmium are released to the environment
from a variety of sources. The largest source of atmospheric  cadmium
(more than 100 Mg/year)  is fossil fuel combustion  (Radian 1985).
Approximately 75% of the fossil fuel emissions come from coal
combustion, the remainder being composed of  industrial,  commercial, and
residential burning of oil or petroleum products. Another significant
source of cadmium emission is the smelting of nonferrous materials
(copper, lead, zinc, and cadmium), which together  result in about
66 Mg/year being released  to air. Approximately 90 Mg of atmospheric
cadmium results from the Incineration of municipal waste and  sewage
treatment sludges. The number of municipal waste  incineration units  is
expected to triple in  the  next  10 years and  municipal  incineration may,
therefore, become an even  larger source. The iron and  steel  industry
produce approximately  10 Mg  from the use of  cadmium-containing  raw
materials. The estimated yearly total cadmium emission rate  in  air is
270 Mg  (Radian 1985).

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 60   Section 6

     The U.S. soils  receive  approximately 680 Mg of cadmium per year
 (EPA 198Sa) from phosphate fertilizer, atmospheric fallout, rainwash,
 irrigation water,  and  landspread sewage sludge. Of these sources, the
 largest  (400 Mg/year)  is phosphate  fertilizer, a contribution that could
 increase markedly  if Western United States fertilizer (with a natural
 cadmium content of 100 Mg/g) takes  a substantially increased market
 share  from Eastern United States fertilizers, which are relatively low
 in cadmium (3 to 20  Mg/g)•

 6.2.2  Natural

     Although overall  natural sources of cadmium are relatively low, the
 metal  is widely distributed  in  the  Earth's crust and is commonly found
 at detectable levels in soil, surface water, and groundwater. Natural
 weathering releases  170 Mg of cadmium to water in the United States
 annually (EPA 198Sa).  Natural atmospheric releases of cadmium are very
 small. In  general, natural sources  of cadmium are rarely of health
 concern.

 6.3  ENVIRONMENTAL FATE

 6.3.1  Atmosphere

     Combustion of coal and petroleum products tends to produce cadmium
 that is adsorbed to  small (1 to  2 /im) particles that are persistent in
 the atmosphere and are easily respirable (EPA 1981). Cadmium released to
 the atmosphere in  particulate matter can be transported some distance
 and transferred to other environmental compartments via wet or dry
 deposition; consequently, the atmosphere provides an important route for
 environmental cadmium  transfer  (Keitz 1980).

     Cadmium compounds usually found in the atmosphere are oxide,
 sulfide, sulfate,   and chloride.  These are stable compounds and do not
 undergo chemical reactions quickly. Significant amounts of cadmium
 carbonate  or organocadmium compounds are not usually present in the
 atmosphere (Keitz  1980).

     Given cadmium's tendency of being concentrated in very small
 particles,  particularly those of fly ash, It is likely to be more
 persistent in the  atmosphere than larger particulate pollutants. The
 transformation of  cadmium compounds in the atmosphere is usually by
 solubility in water and dilute acids. Photochemical reactions are not
 considered to be involved in the atmospheric fate of cadmium (Keitz
 1980).

 6.3.2  Surfme* Water

     Compared to heavy metals such as lead, cadmium is relatively mobile
 in the aqueous environment. In natural waters, cadmium may exist as the
hydrated ion (Cd2+-6H20); as metal-inorganic complexes with C032', OH',
 Cl',  or S042';  or as metal-organic complexes with humic acids. Because
 cadmium exists only in the 2+ oxidation state, aqueous cadmium is not
 strongly influenced by the oxidizing or reducing potential of the water.
However, the sulfide of cadmium  (CdS) has a very low solubility product
 so cadmium sulfide tends to precipitate in sediments under reducing
conditions  that yield sulfide. Exposure of cadmium-containing sediments

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                                                 Environmental Fate   61

to oxygen can result in the oxidation of sulfide and aolubilization of
Cd2+. The concentration of cadaiua in water is usually inversely related
to the pH value and amount of organic material present.  Huaic substances
account for most of the organic complexes, being either soluble or
insoluble depending upon the nature of the huaic substance.  These
products are important because they are more easily assimilated by the
sediments than the free divalent cation. Sorption by clays and iron
oxides is important for reducing the aquatic load of cadmium. Cadmium
does not form volatile compounds in the aquatic environment, nor does
biological methylation occur.

6.3.3  Groundvater
     Several processes tend to keep the concentrations of cadmium low in
groundwater. These include sorption by mineral matter and clay, binding
by huaic substances, precipitation as cadmium sulfide in the presence of
sulfide, and precipitation as the carbonate at relatively high
alkalinities.

6.3.4  Soil
     Cadmium may be present in soil as free cadmium compounds or in
solution as the Cd2+ ion dissolved in soil water. It may also be held to
soil mineral or organic constituents by cation exchange, in which case
it is not readily leached from the soil by rainwater.  The major
reaction for the release of cadaiua held by cation exchange is

             (soil2-)(Cd2+) + 2H+ - (soil2 -)<«+) 2 + Cd2+ ,
where (soil2') represents cation exchange functionalities in the soil.
Thus, high soil acidity favors the release of Cd2+ and its uptake by
plants.  Soil particles containing bound cadaiua may be eroded into air
or water, which results in the spread of cadaiua to the environment.

6.3.5  Biota
     Cadaiua is not reduced or ae thy la ted by microorganisas . Therefore,
in contrast to aercury or arsenic, aicroorganisas do not produce acre
soluble and volatile foras of cadaiua. The biological production of
sulfide, however, results in the precipitation of insoluble cadaiua
sulfide.
     Cadaiua is strongly accuaulated by all organises, both through food
and water. Cadaiua accumulates in freshwater and marine organisms at
concentrations hundreds to thousands of times higher than it in the
water. Lu et al.  (1975) determined that bioaccuaulation of cadaiua was
strongly correlated with the cation exchange capacity of the test soils
in the organises' environaent. As cation exchange increases,
bioaccuaulation of cadaiua decreases. Bioconcentratlon in the aquatic
environaent is greatest for invertebrates like mollusks and crustaceans,
followed by fish  and aquatic plants. Bioaccuaulation of cadaiua in  feed
crops, primarily  a result of cadmium- containing fertilizers, results  in
higher levels of  cadaiua in beef and poultry. The various aspects of
bioaccuaulation of cadmium have important implications for human
exposure .

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                                                                      63
                    7.  POTENTIAL FOR HUMAN EXPOSURE

7.1  OVERVIEW

     Human exposure to cadmium can result from ingestion of water or
food, inhalation of ambient air, smoking, or occupational exposure,
primarily by inhalation. For most people, the ingestion of food is the
largest source of cadmium exposure; however, this is not a health
concern under usual conditions. Most drinking water contains only very
low levels of cadmium and is usually not an important route of exposure,
although there is some tendency for drinking water to pick up cadmium
from plumbing (especially in semisoft water with a low pH).
Concentrations of cadmium in ambient air are generally less than 5
ng/m3, except near pollutant sources.  Municipal incinerators, coal
combustion, and oil burning can contribute cadmium to the atmosphere,
although pollutant emission control measures have reduced the output
from these and other industrial sources. There is some concern that
cadmium levels in soil may be increasing as a result of the application
of municipal sludges or phosphate fertilizers. Increased soil levels may
lead to greater human exposures from food chain accumulation in plants
and animals. Grain and cereal products usually contribute the greatest
percentage of dietary cadmium; potatoes, leafy vegetables, and root
vegetables also contain relatively high levels, as do some shellfish.
Smoking is also an important source of cadmium exposure and may double
an individual's intake of this element.

7.2  LEVELS MONITORED OR ESTIMATED IN THE ENVIRONMENT

7.2.1  Vater

     Because of contamination and the limitations of flame atomic
absorption spectroscopy, it is believed that surveys of the cadmium
content of drinking water taken prior to the mid-1970s have tended to
overestimate concentrations (EPA 1985a). A nationwide survey taken in
1969 (Battelle 1977) showed 63% of drinking water samples exceeding
1 Mg/L, whereas a more recent survey of Canadian drinking waters
(Meranger et al. 1981) gave an arithmetic mean of 0.05 pg/L. Most
drinking waters probably do not contain more than 1 pg/L cadmium (Konz
and Walker 1979). The measurement of low levels of cadmium in drinking
water Is now relatively easy because of the very low detection limits
and high sensitivity of graphite furnace atomic absorption spectroscopy.
     A special case of concern over cadmium in drinking water arises
when the water is soft (lacking calcium and magnesium) and has low
alkalinity. Such water may have a pH as low as 6, or even 5, and tends
to dissolve cadmium and lead from water lines and from soft solder used
in connecting water lines (EPA 1981). Elevated levels of cadmium in
water that has stood for several days in a household distribution system
is evidence of uptake of the metal from plumbing.

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64   Section 7

     There is no evidence in Che literature to suggest that cadmium is a
widespread contaminant of groundwater. A study of 1,063 groundvater
samples taken throughout the state of New Jersey (Page 1981) showed a
median level of 1.0 Mg/L .of cadmium and a high of 405 Mg/L. It is
possible for groundwater*to 'become contaminated with cadmium from
hazardous waste landfill leachate. A study of 30 such leachates from 11
disposal sites showed cadmium (along with iron, calcium,  magnesium, and
arsenic) ranking among the five most abundant inorganic constituents
(Ghassemi et al. 1984); one leachate contained 6,000 pg/L of cadmium.

7.2.2  Air

     Based on a review of a number of surveys of cadmium concentrations
in air around the world, Elinder (198Sa) reported that the average
concentration in ambient air in remote areas of the earth is generally
less than 1 ng/m3. In sparsely populated rural areas, concentrations
typically range from 1 to 5 ng/m3. Cadmium concentrations are more
variable in urban air, depending on the density and nature of industry
in the area, but usually range from about 5 to 40 ng/m3.  Much higher
levels may occur in the vicinity of active zinc or lead smelters, with
values of 300 to 700 ng/m3 at distances of 0.5 to 1 km from the smelter.
The use of emission controls on these facilities has decreased levels
severalfold since 1970 (EPA 1981).

     Elevated levels of cadmium can occur near municipal incinerators,
where average air concentration has been estimated to be -7 ng/m3 (EPA
1979). Incineration of sewage sludge tends to release high levels of
cadmium. However, improved emission controls on incinerators continue to
reduce cadmium output (EPA 1981).  The same can be said for emission
controls on coal-fired and oil-fired power plants.

7.2.3  Soil

     Carey (1979) reported that the concentration of cadmium in U.S.
topsoils typically ranges between 100 and 1,000 pg/kg, with an average
value of 260 ^g/kg. The same value of 260 A*g/kg w*s reported in a survey
of topsoils taken near highways in Maryland, Missouri, and Ohio (EPA
1981). Markedly elevated levels may occur in topsoils near sources of
contamination.  For example, average values of 1,400 Mg/kg were measured
18 to 60 km from a smelter Ln Helena Valley. Montana; 72,000 MgAg 1 k™
from the same smelter; and 1,210 pg/kg in 51 urban soil samples from
Pittsburgh, Pennsylvania (EPA 1981). Topsoil concentrations about twice
those in subsoil may be indicative of topsoil contamination (Pierce et
al. 1982).

     Contamination of topsoil may be indirectly responsible for the
greatest human exposures Co cadmium, mediated through uptake of soil
cadmium into edible plants and tobacco (EPA 1985a). Moreover, levels in
topsoil may be increasing by as much as 1% per year, although such an
increase has not been firmly established. Two major pathways by which
soil becomes contaminated with cadmium are municipal sludge
landspreading and deposition of airborne cadmium (Yost 1983).
Unfortunately,  no practical way is known to decontaminate soil
containing cadmium.

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                                       Potential for Human Exposure   65

7.2.4  Biota and Food
     Cadmium tends co be bioconcentrated by both aquatic and terrestrial
organisms  For some aquatic species, bioconcentration factors (ppm in
the organism on a wet-weight basis divided by ppm in the water) may
range up to 1 0*00 for freshwater and marine plants and up to 3,000 for
freshwater and marine fish (Callahan et al. 1979). Typical
concentrations of cadmium in the flesh of fish from nonpolluted areas
range from 1 to 100 MgAg, and from 70 to 1,200 pgAg f°r shellfish
(Blinder 1985a). The meat of animals typically ranges from 1 to 20 pg/kg
cadmium, with higher levels in the liver and kidneys. Terrestial plants
accumulate cadmium from soil, depending on soil cadmium level, pH,
organic content, and other soil variables. In non-cadmium-polluted
areas, typical levels in leafy vegetables such as lettuce or spinach
range from 12 to 450 MgAg. while values in grains such as rice or wheat
range from 5 to 130 MgAg- Much higher concentrations (up to 2,000
MgAg) »ay occur in plants in cadmium-contaminated areas (Blinder
1985a).

7.2.5  Resulting Background Exposure Levels
     For nonsmoking individuals who are not exposed  to cadmium from
industrial sources, food is generally agreed to be the greatest source
of cadmium exposure. For people in  the United States, the intake  of
cadmium with food has been estimated to range from 10 to 50 jig/day
(Kowal et al. 1979, EPA 1981, Blinder 1985a, Yost 1983, Gartrell  et  al.
1986)  The largest contributor  to dietary  intake  is  plant material,
especially grains and cereals.  Except in atypical situations,  the intake
of cadmium from drinking water  or ambient  air is  of  minor significance.

     The amount of cadmium absorbed from smoking  is  usually  about equal
to the amount absorbed from  the diet. The  concentration of cadmium in
cigarette tobacco is about 1  to 2 Mg/g, and  about 20 to 50%  of the
cadmium  in  inhaled smoke  (10  to 20% of  total  smoke)  is  absorbed.  Thus,
an individual smoking one pack  of cigarettes  per  day might absorb from 1
to 3  ug  cadmium per  day  (Lewis  et al.  1972,  Blinder  1985a).  By
comparison,  dietary  cadmium  levels  are  about 20 Mg/day, °f which  about 5
to 10%  (1 to 2  Mg/day)  is  absorbed. Direct measurement  of cadmium levels
in body  tissues confirms  that smoking roughly doubles cadmium body
burden in comparison to  not  smoking (Lewis ec al. 1972,  Ellis et  al.
1979   Hammer et al.  1973). With regard to kidney, average levels  in
nonsmokers  are  about 15  to 20 jig/g wet weight,  and in smokers, about 30
to 40 pg/g  vet  weight.

7.3  OCCUPATIONAL EXPOSURES
      Based on a survey of occupational hazards in the United States,
N10SH has  estimated that approximately 1,500,000 workers may be exposed
 to cadmium while on the Job (NIOSH 1984a). Sources of worker exposure
 include smelting of lead and zinc ores, mist from cadmium electroplating
vats, drying of cadmium pigments, producing and handling of cadmium
powders, welding or remelting of cadmium-coated  steel  and working with
 solders thac contain cadmium (NIOSH 1984a. Williams and Burson 1985).
 The primary route of occupational exposure is  through inhalation of
 particulate cadmium. Fortunately,  this exposure  can be largely

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66   Section 7

controlled by proper personal protective equipment and through operating
procedures designed to reduce workplace emissions (NIOSH 1976).

7.4  POPULATIONS AT HIGH RISK

7.4.1  Above-Average Exposure

     The greatest potential for above-average exposure is from smoking,
which probably doubles the exposure for most individuals. Smokers with
additional occupational exposure are at highest risk.  A somewhat higher
risk is incurred by individuals living near zinc or lead smelting
operations and other industrial processes that involve cadmium; these
risks have been diminished by industrial pollution control measures.
Above-average ingestion of cadmium-rich foods (kidney, liver,  some fish,
and shellfish) may result in increased exposure, as may ingestion of
grains or vegetables grown in soils that have been applied with
cadmium-rich sludge or fertilizer.

7.4.2  Above-Average Sensitivity

     Differences in individual sensitivity to cadmium have not been
systematically studied, but several factors may possibly be important,
including the following:

   •  Renal disease of other etiology,  which may add to or magnify the
     effect of cadmium on the kidney.

   •  Genetic differences in the induction of metallothionein in response
     to cadmium exposure.

   •  Dietary deficiencies in metal ions and/or protein, which may
     increase cadmium absorption from the gastrointestinal tract.

   •  Age,  with neonates or young children possibly having higher
     gastrointestinal absorption rates than adults.

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                                                                      67
                         8.  ANALYTICAL METHODS
     Atomic absorption spectrometry (AAS) is the most common analytical
procedure for measuring cadmium concentrations in environmental and
biological samples. Other methods include neutron activation analysis
and inductively coupled plasma (ICP) atomic emission spectrometry.
     Samples may be prepared for AAS in a variety of ways. Acid
digestion with nitric acid is most common. Simple dilution with nitric
acid or other agents to solubilize cadmium from the matrix can also be
used. If the concentration of cadmium in the dissolved sample is below
the detection limit, preconcentration techniques, such as chelation or
extraction, may be employed. Since cadmium is a ubiquitous chemical, the
risk of contamination during sampling, processing, and analysis must be
minimized by strict laboratory procedures (Salmela and Vuori 1979).
     The following sections briefly describe methods that are often
employed for measuring cadmium in environmental and biological samples.

8.1  ENVIRONMENTAL MEDIA
     Representative methods appropriate for measuring cadmium in various
environmental media are listed in Table 8.1.

8.1.1  Air
     The American Public Health Association (APHA 1977) Method 311
measures the cadmium content of atmospheric particulate matter. The
method involves filter collection of air samples, ashing and extracting
with a mixture of nitric and hydrochloric acids, and analysis by atomic
absorption spectroscopy. NIOSH Method 7048 also employs air filtration,
acid extraction of the filters, and analysis by atomic absorption
spectroscopy (NIOSH 1984b).

8.1.2  Water
     Three methods standardized by EPA  (1983) are generally used for
cadmium. The atomic absorption furnace  technique has greater sensitivity
than the flame atomic absorption and  inductively coupled  plasma
techniques for cadmium. Techniques to compensate for chemical and matrix
interferences in all three methods are  described  in EPA  (1983). Atomic
fluorescence (Montaser and Crouch 1974)  and colorimetric  (APHA  1985)
methods may also be used.

8.1.3  Soil
     After soils and solid wastes are solubilized  (digested),  they  may
be analyzed for cadmium by  the same AAS methods  described for water
analysis (EPA 1986).

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68    Section  8
                      Tabfcg.1. Analytical i
Sample
matrix
Air

Water

Soil

Food
aAvei
Sample
preparation
Filter collection and
acid extraction
Filter collection
and acid extraction
Acid digestion
Acid digestion
Acid digestion
Acid digestion
Acid digestion
Dry alb/chemical
completing, extract*
Solvent extraction
age percent recovery.
Analytical
method
Atomic absorption
spec troscopy
Flame atomic
absorption
Method 213.1
Atomic absorption/
direct aspiration
Method 213.2
Atomic absorption/
furnace technique
Method 200.7
Inductively coupled
plasnUt atomic
emission ipectrometry
Method 7130
Atomic absorption/
direct aspiration
Method 7131
Atomic absorption/
furnace technique
Atomic absorption
on spectrophotometfy
p mAinr hamm<*al IMnitfflfll
activation
unless noted otherwise.
Sampk
detection
limit
0.005 jig/m1
0.2 Mg/m3
0.005 mg/L
0.1 Mg/L
«»«/L
0.005 mg/L
0.1 Mg/L
SMg/kg*
0.029 Mg/ge

Accuracy" References
90% APHA 1977
NIOSH 1984b
97.8% at EPA 1983
0.071 mg/L
97% EPA 1983
93-116% EPA 1983
EPA 1986
EPA 1986
97.5% Bruhn and
Francke 1976
94-106% Greenberg
et aL 1979

       ^Lowest standard used.
        Lowest concentration found.

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                                                 Analytical Methods   69

8.1.4  Food

     Atomic absorption spectrometry  is  the most common method for
analysis of cadmium  in foods  (Bruhn  and Franke 1976, Dabeka 1979. Muys
1984), but radiochemical  neutron  activation analysis (Greenberg et al.
1979) and differential pulse  anodic  stripping voltammetry  (Satzger et
al. 1982, 1984; Gajan  et  al.  1982) may  also be employed.

8.2  BIOLOGICAL SAMPLES

     Methods for measuring cadmium in biological samples are listed in
Table 8.2.

8.2.1  Fluids and Ezudates

     Cadmium in blood  and urine is usually measured using AAS techniques
(Sharma et al. 1982, Roberts  and  Clark  1986, Subramanian and Meranger
1981,  Subramanian et al.  1983, Stoeppler and Brandt 1980). Atomic
fluorescence spectrometry may also be used (Montaser and Crouch 1974,
Michel et al. 1979).

8.2.2  Tissues

     Lieberman and Kramer (1970)  described a neutron activation
technique for measuring cadmium in muscle, lung, and kidney tissues.
Gross et al. (1976) and Sharma et al. (1982) measured cadmium in hair by
AAS techniques, and Gross et  al.  (1976) measured cadmium concentrations
in soft tissues (liver  and kidney) by AAS, using chelation and
extraction to prepare  the samples for direct aspiration.

     Cadmium in tissues may be measured in vivo by neutron activation
analysis or X-ray fluorescence (Scott and Chettle 1986, Ellis 1985).
Cadmium in the kidney may be  determined by both methods, but liver
cadmium is best measured by neutron activation analysis, since the liver
is a large organ and the  cadmium concentration is usually lower in the
liver than in the kidney  (Scott and Chettle 1986).

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70    Section  8
                        TaMe 8.2.  Analytic*] Betbods for
Sample
matrix
Blood/
plasma



Unne

Hair
Liver
and
kidney

Muscle
"Avei
Sample
preparation
Acid digestion;
chelation and
extraction
Acid digestion;
wet ashing
Nitnc acid
deprotemuation
and matrix
modification
Acid digestion
Di ammonium
hydrogen
phosphate/ mtnc
acid matrix
modification
Acid digestion
Chelation and
extraction
None
Wet ashing

Analytical
method
Atomic absorption
spectroscopy

Atomic absorption
spectroscopy/
graphite furnace
Electrothermal
atomic absorption
spectrophotometry
Atomic absorption
spectroscopy
Atomic absorption
•nectranietrv /
graphite furnace

Atomic absorption
spectnMcopy
Atomic absorption
spectroscopy/
direct aspiration
Neutron activation
analysis, in vivo
Neutron activation
analysis
y unless noted otherwi
Sample
detection
limit Accuracy'

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                                                                      71
                   9.  REGULATORY AND ADVISORY STATUS

     Table 9.1 summarizes regulations and guidelines that apply to
cadmium and inorganic cadmium compounds. These regulations address  air
emissions, occupational exposure concentrations, drinking water levels,
industrial discharges, spill quantities, presence in hazardous wastes,
reporting rules, and pesticide usage.

9 . 1  INTERNATIONAL
     The World Health Organization (WHO 1972, 1984) has recommended a
drinking water guideline value for cadmium of 0.005 mg/L and a
provisional tolerable weekly dietary intake of 0.4 Co 0.5 mg per
individual (-1
9.2  NATIONAL

9.2.1  Regulation*

9.2.1.1  Air
     The EPA Office of Air Quality Planning and Standards (OAQPS), under
authorization from Section 112 of the Clean Air Act, proposes to list
cadmium as a hazardous air pollutant (HAP) . Hazardous air pollutants are
those substances which may reasonably be expected to cause an increase
in mortality or serious  illness  in humans  following significant
exposure .
     The Occupational Safety and Health Administration  (OSHA) sets
permissible exposure limits  (PELs) for occupational exposures to
chemicals based on the recommendations of  the National  Institute for
Occupational Safety and  Health  (NIOSH) . The OSHA PEL for cadmium dust is
0.2 mg/m3 cadmium in workplace  air for a time-weighted average  (TWA)
(8 h/day, 40 h/week) and 0.6 mg/m3 for a ceiling concentration which
shall not be exceeded at any time. The PELs for cadmium fumes, which are
primarily cadmium oxide  fumes,  are 0.1 and 0.3 mg/m3 for the TWA and
ceiling concentration, respectively.

9.2.1.2  Water
     Discharge of cadmium in industrial wastewater  is  regulated by EPA
and some states under  the National  Pollutant  Discharge Elimination
System  (NPDES) and General Pretreatment Regulations.
     The EPA Office  of Drinking Water (ODW) has  promulgated an Interim
Maximum Contaminant  Level (MCL) for cadmium of 0.010 mg/L.  This HCL is
based primarily on a consideration of health effects,  taking cost and
feasibility into  account. ODW is in the  process  of setting a Revised
Primary Drinking  Water MCL for cadmium and,  to that end,  has proposed a

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72
Seccion 9

Agency
WHO


EPA OAQPS
OSHA


AODW
AOWRS


FDA
EPAOERR


EPAOSW

Description
Guideline for dnnkuig water
Provisional tolerable weekly intake
National
Intent to list cadmium as a hazardous
air pollutant
Permissible exposure limit
Time-weighted average (TWA)
Cadmium dust
Cadmium fume (cadmium oxide)
Ceiling
Cadmium dust
Cadmium fume (cadmium oxide)
Maximum contaminant level (MCL) in
drinking water
General permits under the National
Pollutant Discharge Elimination
System (NPDES)
Criteria and standards for the NPDES
General pretreaunent regulations for
existing and new sources of pollution
Permissible level in bottled water
Repoitable quantity
Qgdiniiif»t (<100 j11*1 in diam)
Cadmium acetate
Reportabte quantity (proposed)
Cadmium (<100 urn in diam)
Cadmium chloride
Extremely hazardous substances
threshold planning quantity (TPQ)
Listing as a hanrdnus waste
constituent (Appendix VIII)
(ant otherwise specified)
Application of solid waste to land
used for production of food-chain crops
(interim final)
Value
0005 mg/L
04-03 rag

NA

0.2 mg/m3
0.1 mg/m3
0.6 mg/m3
0.3 mg/m
0.010 mg/L
NA
NA
NA
0.01 mg/L
1 Ib
100 Ib
100 Ib
100 Ib
10 Ib
10 Ib
10 Ib
10 Ib
100-10.000 Ib
1,000-10,000 Ib
NA
0.5 kg /hectare.
annual rate
References
WHO 1984
WHO 1972

SO FR 42000
(10/16/85)
29 CFR 1910


40 CFR 141.11
40 FR 59566
(12/24/75)
40 CFR 122.28
40 CFR 125
40 CFR 403
21 CFR 103.35
40 CFR 3014
50 FR 13456
(04/04/85)
52 FR 8140
(03/16/87)
40 CFR 355
Appendix A
52 FR 13378
(04/22/87)
40 CFR 261
45 FR 33084
(05/19/80)
40 CFR 257.3-5
44 FR 53438
(09/13/79)

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                                               Regulatory and Advisory  Status     73
                                  Table 9.1 (coadnH)
Agency
EPAOTS
EPAOPP
Description Value
Toxic chemical release reporting (proposed) NA
Cadmium
Cadmium compounds
Preliminary determination to cancel NA
registration of pesticides containing
cadmium compounds
References
52 FR 21 152
(06/04/87)
31 FR 36524
(10/10/86)
  NIOSH
  ACGIH
  EPAODW
  NAS





  EPA OWRS



  IARC

  EPA
State eoviron-
meaul agencies
Recommended exposure limit for
occupational exposure to cadmium dust
or cadmium fumes (cadmium oxide)

  TWA
Threshold limit value (TLV)

  TWA
            i dust and salts
    Cadmium oxide production

  Ceiling limit
    Cadmium oxide fume

Maximum contaminant level goal (MCLG)
(proposed)
Health advisories
  1-day
  10-day
  Longer term
    Adult
    Child
  Lifetime
Suggested ao-adverse-effect level
(SNARL)
  Chronic
  7 day.
  Iday
Ambient water quality criteria to protect
human health
  Ingesting water and organisms

Carcinogenic classification

Carcinogenic classification

                   Stm RafaiafioBB)

Water quality standards for several nates
                                                        Lowest
                                                        feasible
                                                        limit
                                       0.05 ng/m1
                                       0.05 mg/m1

                                       0.05 mg/m

                                       0.005 mg/L
                                                        43 Mg/L
                                                        43 Mg/L

                                                        18 Mg/L
                                                        5 Mg/L
                                                        5 Mg/L
                                       0.005 mg/L
                                       0021 mg/L
                                       0.150 mg/L
                                       0.01 mg/L

                                       Group 2B

                                       Group 81



                                       0.01 mg/L
                                                                        NIOSH 1985
                                                                        ACGIH 1986
50 FR 46936
(M/13/85)

EPA 1987b
                                                                        NAS 1982
45 FR 79318
(11/28/80)


IARC 1976

EPA 198Sb
Environment
reporter

-------
 74    Section 9

 Maximum Contaminant Level Goal (MCLG)  of 0.005 mg/L for  cadmium,  based
 on  the WHO and National Academy of Sciences  (NAS)  guidelines.  The MCLG
 is  a nonenforceable goal based on consideration of health  effects only.
 ODV will set the revised MCL as close  to the MCLG  as  feasible,  taking
 cost and technological  factors into consideration  (see Sect.  9.2.2.2).

 9.2.1.3  Reportable quantities

      The Comprehensive  Environmental Response, Compensation,  and
 Liability Act of 1980 (CERCLA) requires  that persons  in  charge  of
 vessels or facilities from vhich a hazardous substance has been released
 in  quantities equal to  or greater than its reportable quantity  (RQ)
 immediately notify  the  National Response Center of  the release. The
 reportable quantities for cadmium and  several cadmium compounds set by
 the EPA Office of Emergency  and Remedial Response  (OERR) are  presented
 in  Table 9.1.  The EPA has proposed changing  the RQ  to 10 Ib for cadmium
 and each cadmium compound.

      Under the Superfund Amendments and  Reauthorization Act of  1986
 (SARA),  EPA published a final  rule (52FR13378), listing extremely
 hazardous substances and corresponding threshold planning quantities
 (TPQs)  for those substances. The TPQs  are intended  to help communities
 focus on the substances and  facilities of the most  immediate  concern for
 emergency planning  and  response,  in case of  accidental spills or
 releases to the  environment. Two cadmium compounds  are included on the
 extremely hazardous substances list, and these are  listed with  their
 TPQs in Table  9.1.  These  compounds are solids and,  therefore, have two
 TPQs:  the first  is  for  solids  in forms which can potentially  result in
 an  airborne release; the  second (10,000  Ib)  is for  solids in  any  other
 form.

      In compliance with SARA,  the  Office of  Toxic Substances  (OTS)
 proposed a rule  requiring manufacturers  and  processors of certain toxic
 chemicals  to report their releases of  those  chemicals to any
 environmental  media. Cadmium and cadmium compounds  are included in this
 rule.

 9.2.1.4  Waste disposal

      Chemicals are  included  on the Resource  Conservation and Recovery
Act  (RCRA)  Appendix VIII  list  of hazardous constituents (40 CFR Part
 261)  if  they have toxic,  carcinogenic, mutagenic,  or teratogenic  effects
on humans  or other life forms.  Cadmium compounds are included on  this
 list  (see  Table  9.1). Vastes containing  cadmium are subject to  the RCRA
regulations promulgated by the  EPA Office of Solid Waste (OSW). These
regulations address generation,  transport, treatment, storage,  and
disposal of hazardous wastes.  The  rate of land application of sewage
sludge and  other solid wastes  containing cadmium to land used for the
production  of  food-chain  crops  is  limited to 0.5 kg/ha annually.  Other
restrictions on  the pH of the waste and  soil mixture and the cumulative
application of cadmium also  apply.

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                                      Regulatory and Advisory Status   75

 9.2.1.5  Pesticide

      The EPA Office of Pesticide Programs (OPP) is responsible for the
 registration of all pesticide products sold in the United States. OPP
 may cancel or modify the terms of registration whenever it is determined
 that the pesticide causes unreasonable adverse effects on the
 environment. OPP has proposed banning the use of cadmium-containing
 pesticides based on determination of significant risk to the
 applicators. These pesticides are currently used as fungicides for turf
 disease control on golf courses.

 9.2.2  Advisory Guidance

      Advisory guidance levels are environmental concentrations
 recommended by either regulatory agencies or other organizations
 protective of human health or aquatic life.  While not enforceable,  these
 levels  may be used as the basis for enforceable standards.  Advisory
 guidance for cadmium is summarized in Table 9.1.  It includes the
 following:  a recommended standard for occupational exposure,  a threshold
 limit value (TLV),  the proposed MCLG for drinking water,  health
 advisories,  ambient water quality criteria,  and Suggested No Adverse
 Response Levels (SNARLs)  calculated by the NAS.

 9.2.2.1  Air

      The NIOSH recommended exposure limit (REL)  for occupational
 exposure to  cadmium dust  or cadmium fumes (cadmium oxide) in air  is the
 lowest  feasible limit,  based on classification of cadmium as  a potential
 human carcinogen.

      The American Conference of Governmental  Industrial Hygienists
 (ACG1H)  recommends  a TLV  TWA of 0.05 mg/m3,  for  cadmium dusts  and salts
 and  for cadmium oxide  production. The ceiling  limit for cadmium oxide
 fumes is also  0.05  mg/m3.

 9.2.2.2  Vater

     As  mentioned earlier,  EPA  has  proposed an MCLG of 0.005 mg/L for
 cadmium.  EPA assumes  that  for carcinogens there  is  no threshold below
 which adverse  effects will  not  occur;  therefore,  the MCLG for
 carcinogens  is  normally zero. Although cadmium has  been classified  as a
 probable  human carcinogen by EPA, the MCLC was not  proposed as  zero
 because  the  evidence of carcinogenicity  is based on inhalation  exposure
 and no  evidence has been  found  linking ingestion of cadmium with
 carcinogenic effects in animals or humans (50  FR 46965). The proposed
 RMCL is based  on NAS and WHO guidelines which  allocate approximately 25%
 of the acceptable daily intake of cadmium to drinking water.

     ODW prepared Health Advisories  (HAs)  for  numerous drinking water
 contaminants. The HAs describe concentrations  of contaminants  in
 drinking water at which adverse effects would  not be anticipated  to
 occur and include a margin of safety to protect sensitive members of the
 population. The HAs are calculated for 1-day,  10-day, longer-term,  and
 lifetime exposures. For cadmium, EPA recommended a  value of 43  Mg/L for
both the 1-day and 10-day HAs for a  child. Appropriate data for deriving
 longer-term HAs were not available,  but ODW suggested using the drinking

-------
 76    Section  9

 water equivalent  level (DWEL)' value  of 18 Mg/L as an appropriate
 longer-term HA  for  an adult.  Adjusting that value for a child yields  a
 longer-term HA  of 5 Mg/L.  Assuming that 25% of the  total permissible
 cadmium exposure  may be  derived from drinking water, ODW calculated the
 lifetime HA to  be 5
      Ambient water  quality criteria  are guidelines set by the EPA Office
 of  Water  Regulations  and Standards  (OWRS) to protect human health from
 potential adverse effects from the  ingestion of water and/or edible
 aquatic organisms (fish  and shellfish) from surface water sources. The
 criterion for  cadmium for ingestion  of water and organisms is 0.01 mg/L
 based on  toxic effects (EPA 1980) . Since this value was identical to the
 existing  drinking water  standard, a  criterion based on exposure from
 ingesting only organisms was not calculated.

      The  NAS calculated  1-day,  7 -day, and chronic SNARLs for cadmium
 based upon its toxicity.  The values  calculated are 0.150 mg/L, 0.021
 mg/L,  and 0.005 mg/L,  respectively.

 9.2.3 Data Analysis
 9.2.3.1   Reference  dose

      A reference dose  (a daily exposure that is estimated to be without
 appreciable human health risk)  of 0.0005 mg/kg/day for oral exposure to
 cadmium in water has been established by the EPA. This value is based on
 the estimate by Friberg  et al.  (1974) that, if absorption is 4.5% and
 renal excretion is  0.01%  per day, then ingestion of 0.35 mg/day (about
 0.005 mgAg/day in  a  70-kg adult) would not exceed the critical renal
 concentration  (200  Mg/g)  after 50 years of exposure. Taking 0.005
 mg/kg/day as a NOAEL  in  humans, the  proposed reference dose was derived
 by dividing by an uncertainty  (safety) factor of 10. Because absorption
 of cadmium from the diet  is  about half that from water, the EPA has also
 established a  separate reference dose (of 0.001 mg/kg/day) for cadmium
 in food.  No reference  dose  for inhalation exposure has been proposed
 (EPA  1987a).

 9.2.3.2   Carcinogenic  potency

      EPA has evaluated the weight of evidence on the carcinogenicity of
 cadmium.   It has concluded that cadmium is a probable human carcinogen
 (Group Bl) by  the inhalation route (EPA 1987a) . This is based on limited
 evidence  of carcinogenicity  from epidemiological studies and the finding
 that  there is  sufficient  evidence of carcinogenicity in animals. There
 are not sufficient  data  to consider  cadmium to be carcinogenic by the
 oral  route (EPA 1987a) .

      EPA  (1985b) has calculated the  excess lung cancer risk associated
with  inhalation exposure  to  cadmium  from two different studies.  Thun et
 al.  (1985) reported a  dose -dependent increase in mortality from
 respiratory cancer  in white  males exposed to cadmium in the workplace,
 and Takenaka et al.  (1983) reported  dose -dependent increases in lung
cancer frequency in rats  exposed to  CdCl2 aerosols. Lung cancer risk
estimates derived from these data are summarized in Table 9.2. Although
 the risk estimate based on the animal data is higher (and hence more
conservative)  than  the risk  estimate based on the human data, the

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                                     Regulatory and Advisory Status   77

Carcinogen Assessment Group considers the latter more relevant, due to
species differences and the type of exposure employed (cadmium salt vs
cadmium fume and cadmium oxide) (EPA 1985b, 1987a).

     Because of the many uncertainties in the cancer risk assessment
procedure, estimates of cancer potency are derived in a way that is
intentionally conservative; that is, true risks could be lover but are
not likely to be higher.

9.3  STATE

9.3.1  Regulations

     State water quality standards are water quality criteria applied to
waters specified for designated uses. Several states have established
specific water quality standards for cadmium for waters designated for
general and/or domestic use. Most states set the water quality standard
for cadmium at 0.01 mg/L, and several states cite the Interim MCL and/or
the EPA Water Quality Criteria as being the guidance for the water
quality standards for toxic pollutants. Regulations from the states were
still being compiled at the time of printing.

9.3.2  Advisory Guidance

     Advisory guidance from the states was still being compiled at the
time of printing.

-------
78    Section 9
                     Table 9.2.  Summary of hmg cancer risk estimates for
                               inhalation exposure to cadmium
                        Parameter
     Rats
(Takenaka et al.
     1983)
                                        Humans
                                       (Thun et al.
                                          1985)
Mathematical
procedure
Unit risk-

  Point estimate
  95% Upper bound
  95% Lower bound

Risk-specific
Concentration*

     Risk level
                                           Linearized
                                           multistage
                                           5.5 X 10~2
                                           9.2 X 10~2
                 Maximum
                 likelihood
                  1.8 X  10~3
                  3.5 X  10~3
                  1.7 X  10~4
                                             Concentration (Mg/m3)
io-4
io-J
1.0 X 10~3
1.0 X 10~4
1.0 X 10~s
2.9 X 10~2
2.9 X 10~3
2.9 X 10~4
                       "The risk associated with lifelong inhalation expo-
                    sure to 1 Mg/m3.
                       *The concentration of cadmium in air associated
                    with a specific excess lifetime risk of lung
                    cancer—calculated using the upper 95% confidence
                    limit from each study.

                       Source: EPA 1985b.

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                                                                      79
                            10.   REFERENCES
ACGIH. 1986. American Conference of Government Industrial Hygienists.
Documentation of the Threshold Limit Values and Biological Exposure
Indices. 5th ed. Cincinnati, OH.

Ades AE, Kazantzis G. 1988. Lung cancer in a non-ferrous smelter:  the
role of cadmium. Br J Ind Med (in press).

Amacher DE, Paillet SC. 1980. Induction of trifluorothymidine-resistant
mutants by metal ions in L5178Y/TKV" cells. Mutat Res 78:279-288.

Andersson K, Elinder CG, Hogstedt C, KJellstrom T. 1982. Mortality Among
Cadmium Workers in the Swedish Battery Factory. Translated from the
article in Swedish entitled "Mortality in Battery Workers Exposed to
Cadmium and Nickel." Report to the Swedish Work Environment Fund.

Aoki A, Hoffer AP. 1978. Reexamination of the lesions in rat testes
caused by cadmium. Biol Reprod 18:579-591.

APHA  (American Public Health Association) 1977. Methods of Air Sampling
and Analysis. 2nd ed. Washington, DC, pp. 894-902.

APHA  (American Public Health Association) 1985. Standard Methods for the
Examination of Water and Wastewater. 16th ed. Washington, DC.

Armstrong BG, Kazantzis G.  1983. The mortality of cadmium workers.
Lancet 1:1425-1427.

Armstrong BG, Kazantzis G.  1985. Prostatic cancer and chronic
respiratory and renal disease in British cadmium workers: A case-control
study. Br J Ind Med 42:540-545.

Axelsson B, Plscator M. 1966. Renal damage after prolonged exposure to
cadmium. An experimental study. Arch Environ Health  12:360-373.

Baltrop D.  1986.  Evaluation of  cadmium exposure from contaminated soil.
In: Ass ink JW, vondenBrink WJ,  eds. Contaminated  Soil.  Dordrecht,  the
Netherlands: Martlnus Nlzhoff Publishers.
*Key  studies.

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80   Section 10

* Baranski B. 1984. Behavioral alterations in offspring of female rats
repeatedly exposed to cadmium oxide by inhalation. Toxicol Lett
22:53-61.

* Baranski B. 1985. Effect of exposure of pregnant rats to cadmium on
prenatal and postnatal development of the young. J Hyg Epidemiol
Microbiol Immunol 29:253-262.

* Baranski B. 1986. Effect of maternal cadmium exposure on postnatal
development and tissue cadmium, copper, and zinc concentrations in rats.
Arch Toxicol 58:255-260.

Baranski B. 1987. Effect of cadmium on prenatal development and on
tissue cadmium, copper, and zinc concentrations in rats.  Environ Res
42:54-62.

* Baranski B, Stekiewicz I, Sitarek K, Szymczak W. 1983.  Effects of oral
subchronic cadmium exposure on fertility, prenatal and postnatal progeny
development in rats. Arch Toxicol 54:297-302.

Barnes D et al. 1987. Reference dose (RfD):  Description and use in
health risk assessment. Appendix A in Integrated Risk Information
Systems Supportive Documentation. Vol. 1. Office of Health and
Environmental Assessment, Environmental Protection Agency, Washington,
DC.  EPA/600/8-86-032a.

Barrett HM, Card BY. 1947. Studies on the toxicity of inhaled cadmium.
11.  The acute lethal dose of cadmium oxide for man.
J Ind Hyg Toxicol 29:286.

* Barrett HM, Irwin DA, Semmons E. 1947.  Studies on the toxicity of
inhaled cadmium. I. The acute toxicity of cadmium oxide by inhalation. J
Ind Hyg Toxicol 29:279.

Battelle. 1977. Multimedia Levels of Cadmium. Environmental Protection
Agency, Office of Toxic Substances. PB 273 198.

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* WHO  (World Health Organization). 1980. Recommended Health-Based  Limits
in Occupational Exposure  to  Heavy Metals.  Geneva.

WHO (World Health Organization). 1984. Guidelines  for  Drinking-Water
Quality. Vol.  1.  Recommendations.  Geneva.

Williams PL, Burson JL,  ed.  1985.  Industrial Toxicology.  Safety and
Health Applications  in the Workplace.  New  York: Van Nostrand Reinhold.

* Wills  JH,  Groblewski GE,  Coulston F.  1981. Chronic  and multigeneration
toxieities of  small concentrations of cadmium  in the  diet of rats.
Ecotoxicol Environ Safety 5:452-464.

Wilson RH, DeEds F,  Cox AJ.  1941.  Effects  of continued cadmium feeding.
J Pharmacol Exp Therap 71:222-235.

Wong  KL, Klaassen CD. 1982.  Neurotoxic effect  of cadmium in young rats.
Toxlcol Appl Pharmacol 63:330-337.

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102   Section 10

Yemagata N, Shlgematsu I. 1970. Cadmium pollution in perspective. Bull
Inst Public Health 19:1.

Yost KJ. 1983. Source-specific exposure mechanisms for environmental
cadmium. In: Wilson D, Volpe RA, eds. Cadmium 83: Edited Proceedings--
Fourth International Cadmium Conference--Munich.  New York, NY: Cadmium
Council.

* Zenick H, Hastings L, Goldsmith M, Nlewenhuls RJ.  1982.  Chronic
cadmium exposure: Relation to male reproductive toxicity and subsequent
fetal outcome. J Toxicol Environ Health 9:377-387.

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                                                                     103
                             11.   GLOSSARY

Acute Exposure -- Exposure to a chemical for a duration of 14 days or
less, as specified in the Toxicological Profiles.

Bioconcentration Factor (BCF)--The quotient of the concentration of a
chemical in aquatic organisms at a specific time or during a discrete
time period of exposure divided by the concentration in the surrounding
water at the same time or during the same time period.

Carcinogen--A chemical capable of inducing cancer.

Ceiling value (CL)--A concentration of a substance that should not be
exceeded, even instantaneously.

Chronic Exposure--Exposure to a chemical for 365 days or more, as
specified in the Toxicological Profiles.

Developmental Toxicity--The occurrence of adverse effects on the
developing organism that may result from exposure to a chemical prior to
conception (either parent), during prenatal development, or postnatally
to the time of sexual maturation. Adverse developmental effects may be
detected at any point in the life span of the organism.

Embryotoxicity and Fetotoxicity--Any toxic effect on the conceptus as a
result of prenatal exposure to a chemical; the distinguishing feature
between the two terms is the stage of development during which the
insult occurred. The terms, as used here, include malformations and
variations, altered growth, and in utero death.

Frank Effect Level (TEL)--That level of exposure which produces a
statistically or biologically significant increase in frequency or
severity of unmistakable adverse effects, such as irreversible
functional impairment or mortality, in an exposed population when
compared with its appropriate control.

EPA  Health Advisory—An estimate of acceptable drinking water levels  for
a chemical substance based on health effects  information.  A health
advisory is not a legally  enforceable federal standard, but serves as
technical guidance to assist federal, state, and local officials.

Immediately Dangerous to Life or Health  (IDLH)—The  maximum
environmental concentration of a contaminant  from which on* could  escape
within  30 min without any  escape-impairing  symptoms  or  irreversible
health  effects.

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104   Section 11

Intermediate Exposure--Exposure to a chemical for a duration of 15-364
days, as specified in the Toxicological Profiles.

Immunologic Toxicity--The occurrence of adverse effects on the immune
system that may result from exposure to environmental agents such as
chemicals.

In vitro--Isolated from the living organism and artificially maintained,
as in a test tube.

In vivo--Occurring within the living organism.

Key Study--An animal or human toxicological study that best illustrates
the nature of the adverse effects produced and the doses associated with
those effects.

Lethal Concentration(LO) (LCLO)--The lowest concentration of a chemical
in air which has been reported to have caused death in humans or
animals.

Lethal Concentration(SO) (LCso)--A calculated concentration of a
chemical in air to which exposure for a specific length of time is
expected to cause death in 50% of a defined experimental animal
population.

Lethal Dose(LO) (LDLO)--The lowest dose of a chemical introduced by a
route other than inhalation that is expected to have caused death in
humans or animals.

Lethal Dose(50) (LDSO)--The dose of a chemical which has been calculated
to cause death in 50% of a defined experimental animal population.

Lovest-Observed-Adverse-Effect Level (LOAEL)--The lowest dose of
chemical in a study or group of studies which produces statistically or
biologically significant increases In frequency or severity of adverse
effects between the exposed population and its appropriate control.

Lovest-Observed-Effect Level (LOEL)--The lowest dose of chemical in a
study or group of studies which produces statistically or biologically
significant increases in frequency or severity of effects between the
exposed population and its appropriate control.

Malformations--Permanent structural changes that may adversely affect
survival,  development,  or function.

Minimal Risk Level--An estimate of daily human exposure to a chemical
that is likely to be without an appreciable risk of deleterious effects
(noncancerous) over a specified duration of exposure.

Mutagen--A substance that causes mutations. A mutation is a change in
the genetic material in a body cell. Mutations can lead to birth
defects, miscarriages,  or cancer.

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                                                          Glossary   105

Naurotoxiclty--The occurrence of adverse effects on the nervous system
following exposure to a chemical.

No-Observed-Adverse-Effect Level (NOAEL)--That dose of chemical at which
there are no statistically or biologically significant increases in
frequency or severity of adverse effects seen between the exposed
population and its appropriate control. Effects may be produced at this
dose, but they are not considered to be adverse.

Mo-Observed-Effect Level (NOEL)--That dose of chemical at which there
are no statistically or biologically significant increases in frequency
or severity of effects seen between the exposed population and its
appropriate control.

Permissible Exposure Limit (PEL)--An allowable exposure level in
workplace air averaged over an 8-h shift.

q *--The upper-bound estimate of the low-dose slope of the dose-response
curve as determined by the multistage procedure. The q^* can be used to
calculate an estimate of carcinogenic potency, the incremental excess
cancer risk per unit of exposure (usually ng/L for water, mgAg/day for
food, and pg/m3 for air).

Reference Dose (RfD)--An estimate  (with uncertainty spanning perhaps an
order of magnitude) of the daily exposure of the human population  to a
potential hazard  that is likely  to be without risk of deleterious
effects during a  lifetime. The RfD is operationally derived from the
NOAEL (from animal and human  studies) by a  consistent application  of
uncertainty factors that reflect various types  of data used to  estimate
RfDs and an additional modifying factor, which  is based  on a
professional judgment of the  entire  database on the chemical. The  RfDs
are not applicable  to nonthreshold effects  such as cancer.

Reportable Quantity (RQ)--The quantity  of  a hazardous  substance that  is
considered reportable under  CERCLA.  Reportable  quantities are:  (1) 1  lb
or greater or  (2) for  selected substances,  an  amount  established by
regulation either under  CERCLA or  under Sect.  311  of  the Clean Water
Act. Quantities  are measured over  a  24-h period.

Reproductive Toxicity--The occurrence of adverse effects on the
reproductive  system that may result  from exposure  to  a chemical.  The
toxicity may be  directed to the reproductive  organs  and/or  the related
endocrine  system. The manifestation of such toxicity may be noted as
alterations  in sexual behavior,  fertility,  pregnancy outcomes,  or
modifications  in other functions that are dependent on the  integrity of
 this system.

Short-Term Exposure Limit (STEL)--The maximum concentration to which
workers can be exposed for up to IS min continually.  No more than four
 excursions are allowed per day. and there must be at least 60 min
between exposure periods.  The daily TLV-TWA may not be exceeded.

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106   Section II

Target Organ ToxicIty--This  term covers  a broad range of adverse effects
on target organs or physiological systems (e.g., renal, cardiovascular)
extending from  those arising through a single limited exposure to those
assumed over a  lifetime  of exposure to a chemical.

Teratogen--A chemical  that causes structural defects that affect the
development of  an organism.

Threshold Limit Value  (TLV)--A concentration of a substance to which
most workers can be exposed  without adverse effect. The TLV may be
expressed as a TWA, as a STEL, or as a CL.

Time-weighted Average  (TWA)--An  allowable exposure concentration
averaged over a normal 8-h workday or 40-h workweek.

Uncertainty Factor (UP)--A factor used In operationally deriving the RfD
from experimental data. UFs  are  intended to account for (1) the
variation in sensitivity among the members of the human population,
(2) the uncertainty in extrapolating animal data to the case of humans,
(3) the uncertainty in extrapolating from data obtained in a study that
is of less than lifetime exposure, and (4) the uncertainty in using
LOAEL data rather than NOAEL data. Usually each of these factors is set
equal to 10.

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                                                                     107
                         APPENDIX:  PEER REVIEW

     A peer review panel was assembled for cadmium. The panel consisted
of the following members: Dr. J. U. Bell, University of Florida;
Dr. M. G. CherIan, University of Western Ontario; and Dr. R. C. Schnell
North Dakota State University. These experts collectively have knowledge
of cadmium's physical and chemical properties, toxicokinetics. key
health end points, mechanisms of action, human and animal exposure, and
quantification of risk to humans. All reviewers were selected in
conformity with the conditions for peer review specified in the
Superfund Amendments and Reauthorization Act of 1986, Section 110.

     A joint panel of scientists from ATSDR and EPA has reviewed the
peer reviewers' comments and determined which comments will be included
in the profile. A listing of the peer reviewers' comments not
incorporated in the profile, with a brief explanation of the rationale
for their exclusion, exists as part of the administrative record for
this compound. A list of databases reviewed and a list of unpublished
documents cited are also included in the administrative record.

     The citation of the peer review panel should not be understood to
imply their approval of the profile's final content. The responsibility
for the content of this profile lies with the Agency for Toxic
Substances and Disease Registry.

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