This Guidance document represented current agency thinking in regards to the available science at the time it was issued. It no longer represents the current state of science and is presented here for the historical record only.
United States Food and Drug Administration
200 C St., S.W.
Washington, D.C. 20204
January 1993
i. AUTHORS AND CONTRIBUTERS
ii. EXECUTIVE SUMMARY
iii. FORWARD
I. STATUTORY AUTHORITY
II. PUBLIC HEALTH STATEMENT
III. SAMPLING OF AND TRACE ELEMENT ANALYSIS IN SHELLFISH
1. Sampling
1.1 Field Sampling Procedure
1.2 Laboratory Sample Preparation
2. Analytical Methodology
2.1 Mineralization
2.2 Determinative Techniques
3. Quality Assurance/Quality Control (QA/QC)
IV. CONSUMPTION AND EXPOSURE ASSESSMENT
1. Shellfish Intake
2. Cadmium Concentrations in Shellfish
3. Cadmium Exposure from Shellfish
4. Background and Relative Source Contribution
to Cadmium Exposure
4.1 Diet
4.2 Water
4.3 Air
4.4 Soil
4.5 Smoking
5. Select Subpopulations
V. HAZARD ASSESSMENT
VI. LEVELS OF CONCERN
VII. REFERENCES
Michael A. Adams, Ph.D.
Chemistry Review Branch, HFS-247
Division of Product Manufacture and Use
Office of Pre-Market Approval
Michael Bolger, Ph.D., D.A.B.T.
Contaminants Standards Monitoring and Programs Branch, HFS-308
Division of Programs and Enforcement Policy
Office of Plant and Dairy Foods and Beverages
Clark D. Carrington, Ph.D., D.A.B.T.
Contaminants Standards Monitoring and Programs Branch, HFS-308
Division of Programs and Enforcement Policy
Office of Plant and Dairy Foods and Beverages
Curtis E. Coker
Special Assistant to the Director, HFS-301
Office of Plant and Dairy Foods and Beverages
Gregory M. Cramer, Ph.D.
Policy and Guidance Branch, HFS-416
Division of Programs and Enforcement Policy
Office of Seafood
Michael J. DiNovi, Ph.D.
Chemistry Review Branch, HFS-247
Division of Product Manufacture and Use
Office of Pre-Market Approval
Scott Dolan
Elemental Research Branch, HFS-338
Division of Pesticides and Industrial Chemicals
Office of Plant and Dairy Foods and Beverages
This document has been developed to satisfy requests from local and state officials for federal guidance regarding the public health significance of cadmium (Cd) in shellfish. (The term "shellfish" is used in a general sense throughout this document and is meant to include both molluscan bivalves and crustacea.) This document is designed to assist local and state health officials in their deliberations concerning the possible need to either issue consumption advisories or to close waters for fishing because of excessive cadmium contamination. The contents of this document include sections on FDA's statutory authority, a public health statement, sampling techniques and trace element analysis, consumption and exposure information, hazard assessment, and a discussion of estimating levels of concern for local consumption advisories or water closures.
Cadmium is widely distributed at low levels in the environment
and is, from present knowledge, not an essential element for
humans, animals or plants. The sources for human exposure are
air, water, food, and tobacco with food representing the major
route of uptake for the general public. Most foods have an
inherently low level of cadmium with the exception of shellfish
which have been shown to bind cadmium with a protein and
accumulate it at a significantly higher level. Data from the FDA
Total Diet Study (which does not include shellfish) suggest that
the mean lifetime exposure to total cadmium from all food
(excluding shellfish) is 10 
g/person/day. Green leafy
vegetables, potatoes, liver, and milk are major sources of
cadmium in the diet. Cigarettes are a major source of cadmium
exposure. Cadmium exposure among smokers is about 10
g/person/day higher (or about 20 g/person/day) than for
non-smokers. Considering that nonsmokers living with smokers may
be somewhat less exposed to the same contaminants, passive
exposure to tobacco smoke may also be a source of cadmium
exposure.
Cadmium is deposited in the soft tissues of the body with 50-70%
accumulating in the kidney and liver. Accumulation of low levels
is tolerated by the body. However, long term chronic exposure
may result in the accumulation of toxic levels of cadmium in the
kidney. Chronic exposure leads to kidney dysfunction. Blood-
cadmium level is the best measurement of an acute exposure. On
the other hand, measurement of cadmium levels in the urine
represent the best measurement for total body burden. Cadmium
absorbed by the human body is eliminated slowly, with a
biological half-life estimated to be 10-30 years. The World
Health Organization/Food and Agricultural Organization (WHO/FAO)
(WHO, 1989) has determined a maximum tolerable weekly intake of
7 g Cd/kg (about 60 g/person/day for a 60 kg person). A
maximum tolerable daily intake figure of 55 g/person/day is
suggested in this document.
Surveys of contaminants in shellfish conducted by FDA and the
National Marine Fisheries Service have found mean cadmium levels
ranging from 0.1 ppm up to 2.0 ppm. FDA has combined these
survey results with nationally representative shellfish
consumption information to estimate the range of cadmium
exposures that is possible among shellfish consumers. For
individuals who chronically consume an average of 15 g/day of
molluscan bivalves (90th percentile average intake over 14-days
for consumers among survey population) that have mean cadmium
levels of 0.6 ppm, cadmium intake will average 9
g/person/day. For people consuming an average of 17 g/day of
crustacean shellfish (90th percentile average intake over 14-days
for consumers among survey population) that contain mean cadmium
levels of 0.2 ppm, cadmium intake will average 3
g/person/day.
Local patterns of shellfish consumption and/or the levels of
cadmium contamination may vary from national averages. Hence,
cadmium exposures from shellfish in particular regions may also
vary from values estimated using national figures. In order to
decide whether local cadmium exposure levels are of concern, it
is suggested that the maximum tolerable daily intake for cadmium
(55 g/person/day) be used to calculate Levels of Concern,
either maximum permitted amounts of chronic shellfish consumption
or maximum permitted levels of cadmium contamination.
Although local figures for shellfish consumption or shellfish
contamination would be most appropriate for evaluating local
situations, reference to national figures may also prove useful.
As an example, if it is assumed that total cadmium exposure is
derived solely from shellfish, it is calculated that the
cadmium level of concern for individuals consuming molluscan bivalves
on a chronic basis at the 90th percentile average among eaters (15
g/person/day) would be 3.7 ppm. The corresponding consumption level
of concern for individuals consuming molluscan bivalves with cadmium
levels equivalent to the highest average found in one of the national surveys
(2 ppm) is 28 g/person/day.
If other sources of cadmium exposure are to be considered (e.g.,
relative source contribution including other dietary sources of
cadmium), then corresponding adjustments in the levels of concern
will need to be made. Considering that there is only a small
margin of safety between non-shellfish cadmium exposures (10-20
g/person/day) and the tolerable daily intake (55
g/person/day), adjustments for non-shellfish cadmium
exposures will reduce considerably estimates of both the cadmium
levels of concern as well as the consumption levels of
concern.
Purpose
Over the years, and particularly of late, concern has been raised regarding the public health significance of the presence of contaminants in shellfish in both fresh water and marine species. Local and state officials have repeatedly sought guidance at the federal level on these matters; in particular, the advice and position of the U.S. Food and Drug Administration (FDA) has often been requested. FDA is developing a series of guidance documents in an attempt to satisfy the requests for federal guidance. They are designed to assist local and state health officials in their deliberations concerning contaminants in shellfish and the possible need to either issue fish consumption advisories or to close waters for fishing. The term "shellfish" is used in a general sense throughout these documents and is meant to include both molluscan bivalves and crustacea.
Standards have been developed for those contaminants which have been identified as national problems (e.g. methylmercury). Guidance documents have been and will continue to be developed for contaminants which could cause health effects, based on the toxicity of the contaminant and potential exposure. These health effects generally have a low probability of occurring. In some localities, however, adverse health effects may occur under extreme conditions of exposure. Should such conditions exist or occur the information in this guidance document indicates how tolerable levels of shellfish consumption or contamination might be determined; however, it does not dictate an approach or decision regarding a particular contaminant in shellfish. These guidance documents have no statutory authority. They merely present the relevant scientific information on each contaminant. How this information is used is entirely up to public health officials who consult them and may in large part be determined by the particular circumstances of each case.
Based on conclusions reached from a meeting with representatives of state public health organizations, the decision was made not to develop a single advisory level. Instead, a broad guidance approach was developed to address the relevant information on a contaminant so that the information can be used as part of the overall determination of the public health significance of contaminants in shellfish.
Selection of Contaminants
The first guidance documents (for arsenic, cadmium, chromium, lead, and nickel) address contaminants chosen because they are most likely to occur and frequent concerns have been raised regarding their presence in shellfish. Concern about these elements is to be expected, since shellfish tend to accumulate elemental contaminants present in the environment.
Relevant Statutory Authority
The guidance documents were developed with a clear understanding of the statutory responsibilities of the Environmental Protection Agency (EPA) (e.g. Clean Water Act), the FDA, and the states. There is no intent to circumvent the statutory authority of any state or federal authority.
Scope
These guidance documents have been designed for use by public health officials at the federal, state and local level, other interested parties and members of the general public. These documents are being issued to present FDA's assessment of the current state of knowledge on specific contaminants and they will be revised when important new information becomes available. The agency requests and strongly encourages anyone with relevant information to add to these documents to contact the Office of Seafood at the address shown on the cover of this document.
Each guidance document begins with a public health statement much like that given in the toxicological profiles published by the Agency for Toxic Substances and Disease Registry (ATSDR). The sections that follow present information about sampling shellfish, analytical procedures for analysis of elemental contaminants in shellfish, consumption and exposure assessments, and conclude with a summary of toxicological and adverse effects of these contaminants. Each document identifies and summarizes the key literature describing the information, including the work of other health organizations (e.g toxicological profiles - ATSDR and environmental health criteria -International Program on Chemical Safety/World Health Organization).
The purpose of the Federal Food, Drug, and Cosmetic Act (FD&C Act) is to ensure a safe and wholesome food supply. The FD&C Act and other related statutes, including the Public Health Service Act, provide the regulatory framework under which the Food and Drug Administration assesses the effects of environmental contaminants on the safety of consumption of fish and shellfish (molluscan bivalves and crustacea). FDA has jurisdiction over foods that are intended for introduction into, or have been shipped in interstate commerce.
The basic provision of the Act dealing with poisonous or deleterious substances in food is section 402(a)(1). This section states:
-(a)(1) if it bears or contains any poisonous
or deleterious substance which may render it
injurious to health; but in case the
substance is not an added substance such food
shall not be considered adulterated under
this clause if the quantity of such substance
in such food does not ordinarily render it
injurious to health;This section applies to all poisonous or deleterious substances, whether they are naturally occurring or added.
Section 402(a) (1) of the Act distinguishes between naturally occurring and "added" substances and sets different standards for each. Naturally occurring substances would adulterate a food only if they render the food "ordinarily" injurious to health. Added substances would adulterate the food if the food "may" be injurious to health.
The term "added" in this legal context is important. An added poisonous or deleterious substance is a substance that does not occur naturally in foods. A "naturally occurring poisonous and deleterious substance" is a substance that is an inherent, natural constituent of a food and is not the result of environmental, agricultural, industrial, or other types of contamination. When a naturally occurring, poisonous, or deleterious substance is increased to abnormal levels through mishandling or other intervening acts, it is regarded as an added substance.
Under conditions where an unavoidable contaminant occurs at a level that is of concern to FDA, FDA may establish a formal tolerance limiting the extent of allowable contamination of a food. Compliance with a tolerance is strictly determined on the basis of the results of analysis of commingled representative subsamples of edible portions taken from a fish shipment, not on the basis of a single fish. However, when toxicological data are scanty or conflicting, when additional data are being developed, or when other conditions are rapidly changing, FDA may choose not to establish a tolerance. Nevertheless, it may still be appropriate to take some regulatory action to control exposure to a contaminant. In such circumstances, FDA may consider developing guidelines or regulatory limits.
The authority of the FD&C Act extends only to fish and shellfish that are moving in interstate commerce. Accordingly, tolerances and guidelines are typically established on a national basis when it is judged that a national problem exists for a particular contaminant. Thus, guidelines are generally, but not always,tailored to national needs and national patterns of consumption. For example, consumption levels of fish on a national per capita basis are generally considerably less than those typical of sports fishermen or of individuals living near lake shores or coastal regions of the U.S. Nonetheless, the toxicity information {Reference Dose, (RFD) or Acceptable Daily Intake (ADI)} that is considered in the setting of national guidelines, may be useful to the states in establishing local controls or advisories on local shellfish consumption. If a potential local health threat exists, a state or locality may wish to issue warnings or provide guidance on the quantity of contaminated shellfish that may be safely consumed. Local authorities can utilize the available federal toxicity information and compare it with the level of the contaminant found locally and local shellfish consumption patterns to establish acceptable levels.
Cadmium is widely distributed at low levels in the environment and is, from present knowledge, not an essential element for humans, animals or plants. Global emissions of cadmium compounds arise principally from point industrial sources including combustion of fossil fuels, waste slag, phosphate fertilizers, and sewage sludge. Other sources of exposure to cadmium arise from the recycling and incineration of municipal solid waste and hazardous wastes. The sources for human exposure are air, water, food, and tobacco with food representing the major route of uptake for the general public.
Cadmium emitted into the atmosphere from smelters, waste incineration plants, and other sources occurs mainly in the form of small aerosol particles (< 2 m dia) which are inhaled and reach the lower airways of humans and animals.
The levels of cadmium in the body at birth are very low due to
little, if any, absorption from maternal sources. In most
individuals, body cadmium levels begin to increase shortly after
birth from the introduction of solid food. Most foods have an
inherently low level of cadmium with the exception of shellfish
which have been shown to bind cadmium with a protein and
accumulate it at a significantly higher level. Data from the FDA
Total Diet Study (which does not include shellfish) suggest that
the mean lifetime exposure to total cadmium from all food
(excluding shellfish) is 10 g/person/day. Since cadmium is
widely distributed in the environment, and cadmium intake from
all sources exceeds the slow rate at which cadmium is excreted,
the body burden (tissue accumulation) steadily increases
throughout an individual's lifetime.
In mammals, cadmium is bound predominantly to metallothionein, the biosynthesis of which is induced by cadmium. Cadmium is deposited mainly in the kidneys and liver. In whole blood, cadmium is bound to the erythrocytes. Cadmium is deposited in the soft tissues of the body with 50-70% accumulating in the kidney and liver. Accumulation of low levels are tolerated by the body, however, long term chronic exposure may result in the accumulation of toxic levels of cadmium in the kidney. Chronic exposure leads to kidney dysfunction. Blood-cadmium levels are the best measurement of an acute exposure, however, measurement of cadmium levels in the urine represent the best measurement for total body burden. There is no effective treatment for removing cadmium from the tissues. The pathophysiological effects associated with severe cadmium toxicity are essentially irreversible.
Cadmium absorbed by the human body is eliminated slowly, with a biological half-life estimated to be 10-30 years. Younger individuals absorb and may even proportionally accumulate more cadmium than older ones. Diets that are low in calcium, iron, or protein may lead to enhanced cadmium absorption. Renal damage caused by cadmium is exhibited by an increased urinary excretion of the protein B2-microglobulin.
The World Health Organization/Food and Agricultural Organization
(WHO/FAO) has determined a maximum tolerable weekly intake of 7 g Cd/kg
(or about 60 g/day for a 60 kg person) (WHO, 1989). A maximum tolerable
daily intake of 55 g/person/day is suggested in this document.
III.
In this section methods for the determination of elemental contaminants in shellfish are examined. Necessary steps for shellfish analysis are outlined without repeating published methodologies. Specific analytical procedures are cited.
1. Sampling
Collecting, processing, preserving, and shipping primary samples are the critical steps required for generating valid analytical data. A detailed sampling plan for proposed specific sample collection sites should be developed before actual collection is started. The plan should include site locations, target species, target contaminants, sampling times, types of samples, and sample replication. Samples must be representative of the site or lot being studied. In addition, these steps must be conducted in a manner that preserves the integrity of the analyte(s) of interest and precludes inadvertent contamination (EPA, 1991). If sampling of processed shellfish products is required, specific sampling procedures can be found in the FDA Inspection Operations Manual (FDA, 1990).
1.1 Field Sampling Procedure
A minimum of 3 replicate composite samples from each sampling location is recommended for a representative site or lot. The shellfish collected should satisfy any legal requirements for harvestable size or weight or be of consumable or "market" size when no legal harvestable requirements are in effect. Selection of the largest animals is recommended if a worst-case exposure sampling is desired (EPA, 1991).
Animals used in composited samples should be of similar size with the total length (size) of the smallest animal having no less than 75 percent of the total length (size) of the largest animal. Composites should be composed of equal numbers of from 10 to 50 animals (depending on the species and size class being sampled) for a total minimum weight of 500 g of tissue homogenate. The relative difference (in percent) between the overall mean length (size) of replicate composites and the mean length (size) of any individual composite should be no greater than 10 percent (EPA In progress).
1.2 Laboratory Sample Preparation
Shellfish should be preserved with ice if they are not processed immediately. If shellfish are shipped or stored more than 24 h before processing, dry ice must be used. All laboratory samples should be prepared and analyzed, or frozen, as soon as possible after collection, preferably within 48 h. All instruments, work surfaces, and containers used in processing laboratory samples must be composed of materials that can be easily cleaned and that are not themselves potential sources of contamination. To avoid cross-contamination, all equipment used in sample handling should be cleaned before each test sample (EPA, 1991). Cleaning plastic equipment for trace element analysis has been studied and guidelines are given by Moody and Lindstrom (1977).
Equipment should be chosen to minimize contamination. Contamination may be minimized by using titanium, aluminum, quartz, TFE (tetraflouroethylene), polypropylene, or polyethylene utensils, and a glass blender or food processor with titanium or stainless steel blades and Teflon, polyethylene, or polystyrene gaskets (FDA, 1975). Stainless steel that is resistant to corrosion may be used if necessary. Stainless steel scalpels have been found not to contaminate mussel samples (Stephenson et al., 1979). However, other biological tissues (e.g., fish muscle) containing low concentrations of heavy metals may be contaminated significantly by any exposure to stainless steel (EPA, 1991). The predominant metal contaminants from stainless steel are chromium and nickel. Titanium utensils have been used successfully and are available commercially (Zeisler et al.,1988; Private Communication 1). Aluminum is also an option to consider, especially if it is not an element being studied. Titanium and aluminum each have the advantage of contaminating the sample with only one element. Quartz utensils are ideal but expensive. The analyst must know the elements of interest and their approximate levels in the species to be analyzed in order to make an informed decision about utensil selection.
Before shellfish are "shucked" (opened), the external shell surface should be thoroughly cleaned with brush and water to remove all sand, dirt, etc., adhering to the shell to prevent contamination of composite samples. After shellfish are shucked, the meat and liquor are carefully removed from the shell and collected to minimize incorporation of shell fragments and sand into the test sample. The presence of shell fragments or sand will complicate mineralization. Separation can be accomplished by transferring the meat and decanting the liquor, leaving sand and shell fragments behind. For analysis of canned, frozen, or otherwise processed products, the test sample should include meats, liquor, and any breading. Thaw frozen products prior to homogenization (McMahon and Hardin, 1968). Once shellfish are frozen, thawing of shellfish samples should be kept at a minimum during tissue removal procedures to avoid loss of liquids.
Comminute entire test sample in a glass blender or food processor to obtain a homogeneous mixture. When a food processor is used, adding dry ice successfully freezes the suspension and minimizes water separation. Precaution: If dry ice is used, check dry ice for interferences and store frozen test samples loosely covered overnight to allow for dissipation of carbon dioxide. Composite test samples should be homogenized to a paste-like consistency before portions are taken for analysis. Store prepared test samples frozen in glass jars with Teflon-lined lids or in Teflon containers. If analysis is not started immediately after homogenization, appropriate analytical portions may be weighed and stored frozen. This will eliminate the need to rehomogenize a thawed test sample.
2. Analytical Methodology
Review of the literature reveals that many inorganic analytical studies of shellfish have been prompted largely by a concern that abnormally high levels of toxic elements contaminate some of the world's shellfish growing areas (Marcus and Thompson 1986; Lytle and Lytle, 1982; Watling and Watling, 1982; May and McKinney, 1981; Micallef and Tyler,1989; Balogh, 1988; Eisenberg and Topping, 1984; Gault et al., 1983; Meeus-Verdinne, 1983; Favretto et al., 1981; Cooper et al., 1982).
This concern has focused mainly on elements of biological interest including antimony, arsenic, cadmium, chromium, copper, lead, manganese, mercury, molybdenum, nickel, selenium, tin, and zinc. Various techniques have been applied to analysis of shellfish; however, in the laboratories surveyed (Private Communications 2-5) routine shellfish analysis is conducted usually by using only a few methods. Most methods of shellfish analysis require mineralization of test portions. The digestion procedures can then be coupled with the determinative techniques presented in 2.2 of this section to form complete analytical methods.
2.1 Mineralization
Digestion procedures fall into one of two general categories, dry ash or wet ash. Dry ash digestions use a long, slow ashing step, usually performed overnight in a muffle furnace. The ashing process is completed by the addition of a small quantity of inorganic acid to the residue and evaporation on a hot plate. The residue is redissolved in acid and the solution is brought to volume with distilled or deionized water. Dry ash procedures can be found in the Association of Official Analytical Chemists (AOAC) method 972.23 (Helrich, 1990). Element loss during the ashing process is greater for dry ash procedures than for wet ash procedures. "Ashing aids" are often employed to prevent loss of the more volatile elements like arsenic and selenium (Maher, 1983; May, 1982).
Wet ash digestions are characterized by short ashing times (normally 3 to 4 h) and the use of acids (HCl, HNO3, H2SO4, HClO4). Wet ashing is performed by adding acid or an acid mixture to the test portion and boiling until digestion is complete. A variety of procedures have been developed using different types of digestion apparatus to retain volatile elements. The most common procedure is performed in beakers on a hot plate. The analytical portion is boiled with HNO3 or a mixture of HNO3 and HCl until digestion is complete (FDA, 1975; ASTM, 1986). Combinations of HNO3, HClO4, and H2SO4 have also been used for more efficient oxidation. Perchloric acid requires constant operator attention, specialized equipment (HClO4 hoods, fume traps, etc.), and safety precautions (Michie et al., 1978).
"Hot-block" digesters have been used for improved temperature control and their reflux capabilities (Agemian et al., 1980). "PTFE (polytetrafluoroethylene) bomb" digesters have been used because digestion can take place in a sealed vessel, thereby retaining volatile elements (Welz and Melcher, 1985).
Another wet ash approach that has been applied to fish analysis is microwave digestion (Schnitzer et al., 1988; Nadkarni, 1984; McCarthy and Ellis, 1991). This technique has been subject to extensive research and development since microwave technology was first applied to digestions (Abu-Samra et al., 1975; Barrett et al., 1978; Nadkarni, 1984; White and Douthit,1985; Kingston and Jassie, 1986, 1988; Burguera et al., 1986; Fernando et al., 1986). Current systems incorporate many features to improve digestion time, element recoveries, contamination, and safety. Improved recoveries can be achieved with systems operating under power-regulated control of pressure because these systems allow digestions to be completed without venting volatile elements. Sealed digestion vessels also reduce acid consumption and, in combination with Teflon construction, reduce contamination problems. Microwave digestion methods developed for shellfish do not require HClO4 to complete mineralization. Microwave digestion has been compared to some of the other digestion procedures (Blust et al., 1988).
Regardless of the digestion procedure selected, appropriate quality assurance and quality control guidelines need to be followed. These include the use of contamination control, digestion blanks, spiked test portions, replicate analyses, an appropriate standard reference material (e.g., National Institute of Standards and Technology: Oyster or Bovine Liver), and recovery calculations (Boyer and Horwitz, 1986; Jones, 1988).
2.2 Determinative Techniques
Selection of a determinative technique is often dictated by available equipment and quantitation requirements. Ease of operation, number of analyses, and familiarity of personnel with techniques are also influential factors. For these reasons only a few methods developed for shellfish analysis are used for routine testing. Spectrometric techniques are most commonly used and include flame atomic absorption spectrometry (FAAS), graphite furnace atomic absorption spectrometry (GFAAS), and inductively coupled plasma-atomic emission spectrometry (ICP-AES) (see Table 1).
FAAS is often used to determine many elements in shellfish analysis because it is easy and affordable (Private Communications 2-5). The American Society for Testing and Materials (ASTM) method D3559 (ASTM, 1986) and the American Public Health Association (APHA) method 303 (APHA, 1986) both use FAAS. FAAS has been combined with high-performance liquid chromatography (HPLC) for the study of metal ion speciation in biological systems. Information about the distribution of metal ions in biological extracts can be used to estimate exposure of an animal to chemical toxins, and to estimate the relationship between chemical form and bioavailability (Guy, 1985).
FAAS has been applied to two methods to improve detection of some elements. First, measurement of arsenic and lead has been improved by on-line generation of volatile hydrides with hydride generation-AAS (HG-AAS) (Holak, 1969). In applications of hydride generation to fish analysis, (Agemian and Thompson, 1980; Julshamn et al., 1982; Cutter, 1985; Maher, 1982, 1986; Madrid et al., 1988) the enhancement of detection limits ranged from a factor of 5 to a factor of over 500 (see Table 1). Hydride generation (HG) has also been coupled with GFAAS (Willie et al., 1986; Sturgeon et al., 1986), direct current plasma-AES (DCP-AES) (Panaro and Krull, 1984), and ICP-AES (de Oliveira et al., 1983; Montaser and Golightly, 1987). HG-AAS has been coupled with HPLC for determination of inorganic and methylated arsenic species in marine samples (Maher, 1981).
GFAAS has been used for measurement of selected elements when FAAS determination limits were insufficient for shellfish analysis (Cruz et al., 1980;Serra and Serrano, 1984). Clearly, GFAAS is more sensitive than FAAS although GFAAS analysis time is longer. The main problems with GFAAS shellfish analysis are matrix and spectral interferences. Deuterium arc and Zeeman-effect background corrections have been applied to reduce spectral interference in shellfish analysis. While deuterium arc background correction is plagued by spectral interferences, Zeeman-effect background correction appears to be satisfactory for routine analysis of marine biological tissue (Welz and Schlemmer, 1986; McMahon et al., 1985). Various "matrix modifiers" (organic and inorganic reagents) have been used to reduce matrix effects. Molybdenum, lanthanum, and ammonium dihydrogen phosphate have been used as matrix modifiers for shellfish analysis (Poldoski, 1980; Mckie, 1987). Solvent extraction is another approach taken to minimize matrix effects (Stephenson and Smith, 1988; Harms, 1985).
Solid sampling has been developed for GFAAS to increase relative sensitivity by avoiding the large dilution factors required in the sample dissolution. Solid sampling also eliminates contamination and/or loss of analyte resulting from dissolution. Solid sampling has not been widely used for shellfish analysis because of possible interference by very large background matrix absorbance (Chakrabarti, 1979; May and Brumbaugh, 1982). A complete analysis by GFAAS can be found in ASTM method D3559 (ASTM, 1986).
ICP-AES has also been used for routine elemental analysis of shellfish (Grant and Ellis, 1988). Sequential or simultaneous mode ICP-AES allows rapid analysis, dramatically improving throughput. Detection limits in ICP-AES are generally the same as those in FAAS except for elements that are difficult to atomize. Such elements have lower ICP-AES detection limits because of the higher temperature of the plasma (see Table 1). A complete analysis by ICP-AES can be found in the EPA's water method 200.7 (EPA, 1979).
Although not widely used for routine shellfish analysis, techniques have been developed using voltammetry for trace element determination (ASTM, 1986; Adeloju and Bond, 1983; Breyer and Gilbert, 1987), polarography (Lemly, 1982), ICP-MS (Munro et al., 1986; Beauchemin et al., 1988; Park et al., 1987), HPLC with electrochemical and spectrophotometric detection (Bond and Nagaosa, 1985), and neutron activation analysis (NAA) (Zeisler et al., 1988; LaTouche et al., 1981; DeSilva and Chatt, 1982; Chisela and Bratter, 1986).
Regardless of the analytical method chosen, sound scientific analytical principles must be followed. All methods used by a laboratory must be validated by the laboratory prior to routine sample analysis. The detection and quantitation limits, and accuracy and precision of each method must be assessed and documented to be sufficient for reliable quantitation at or below the level of interest for each metal. All analytical methods used routinely for the analysis of shellfish should be documented thoroughly; formal standard operating procedures (SOP's) are preferred. A published method may serve as an analytical SOP only if the analysis is performed exactly as described. Analytical SOP's should be followed as written (EPA, 1991).
3. Quality Assurance/Quality Control (QA/QC)
Initial demonstration of laboratory capability and routine analysis of appropriate QA/QC samples to document data quality and to demonstrate continued acceptable performance is essential. QA/QC requirements should be based on specific performance criteria, or control limits, for data quality indicators, such as accuracy and precision. Typically, control limits for accuracy are based on the historical mean recovery plus or minus three standard deviation units, and control limits for precision are based on the historical standard deviation or coefficient of variation (or mean relative percent difference for duplicate samples) plus three standard deviation units. Some recommended QA/QC procedures include: instrument calibration and calibration checks, assessment of method detection and quantitation limits, assessment of method accuracy and precision, routine monitoring of interferences and contamination, regular external QA assessment of analytical performanceinterlaboratory comparison programs, appropriate documentation, and reporting of data (including QA/QC data) (EPA, 1991).
Table 1. Quantitation Limits (
ICP-AES FAAS GFAAS(f) Solution Hydride Solution Hydride Element neb.(b) gen.(c) neb.(d) gen.(e)
As 0.5 0.008 10.0 0.03 0.01 Cd 0.05 0.007 0.0005 Cr 0.3 0.20 0.003 Ni 0.2 0.3 0.02 Pb 0.8 0.03 0.3 0.003 0.005 (a) Quantitation limits (10 sigma) were estimated from instrumental detection limits (3 sigma), and a 5 g test portion in 50 ml of test solution was assumed. (b) Values for pneumatic nebulizer/ICP-AES are taken from Applied Research Laboratories literature on Model 3580 OES. (c) Values are reported in Montaser and Golightly (1987). (d) Values are taken from Varian literature on Models AA-1275 and AA-1475 best value was selected for either C2H2-air or C2H2-N2O flame. (e) Value for arsenic are reported in Robbins and Caruso (1979); value for lead in Ikeda et al. (1982). (f) Values are taken from Varian literature on Model Spectra AA-300 (nominal 20 uL injection).
The following sections provide estimates of chronic shellfish intake as well as estimates of cadmium exposure resulting from chronic shellfish consumption. In addition, estimates of cadmium exposure are provided for background sources, both dietary (i.e., non-seafood) and non-dietary sources.
1. Shellfish Intake
The frequency of shellfish eating occasions has been tabulated in the Market Research Corporation of America (MRCA) 14-day survey (5-Year Menu Census, 1982-87) (MRCA, 1988). The MRCA reports that only 13% of the surveyed population consumed crustaceans and only 4.8% of the surveyed population (25,726 individuals, 2+ years) consumed molluscan bivalves. Using standard portion sizes from the USDA's 3-day National Food Consumption Survey (NFCS, 1977-78) (Pao et al., 1982), we estimate the 14-day-average mean and 90th percentile daily intakes of molluscan bivalves. These are presented in Table 2. The intakes for crustacean shellfish are presented in Table 3.
Table 2. 14-Day average intake of molluscan bivalves, grams/person/day, for eaters-only.
Age Group Mean 90th Percentile
2+ years (all ages) 10 15 2-5 years 4 8* (male/female) 18-44 years** 12 18 (male/female) * Estimated value. Reliable data are not available in the MRCA survey. The 90th percentile value is estimated to be twice the mean (WHO, 1983). ** USDA portion size for 33-44 year age group used in the calculation. This age subgroup has the highest consumption of any subgroup in the 18-44 year range. (Pao et al., 1982)Table 3. 14-Day-average intake of crustacean shellfish, grams/person/day, for eaters-only.
Age Group Mean 90th Percentile
2+ years (all ages) 9 17 2-5 years 5 10 (male/female) 18-44 years* 9 19 (male/female) * USDA portion size for 33-44 year age group used in the calculation. This age subgroup has the highest consumption of any subgroup in the 18-44 year range (Pao et al., 1982)
2. Cadmium Concentrations in Shellfish
The National Oceanic and Atmospheric Administration (NOAA) mussel watch project progress report (NOAA, 1989) indicates that none of the mussels and oysters in the 169 sites examined in 1988 exhibited an average cadmium concentration in excess of 1.6 ppm wet weight. The following factors were used for converting dry weight concentrations reported by NOAA to wet weight values: C. virginica, 0.124; M. edulis, 0.121; M. californianus, 0.140; O. sandvicensis, 0.146 (Private Communication 7, 1990).
In 1985-86 the FDA surveyed the levels of cadmium in softshell clams (Mya arenaria), hardshell clams (Mercenaria mercenaria), Eastern oysters (Crassostrea virginica) and Pacific oysters (C. gigas) (S. Capar, FDA, Division of Contaminants Chemistry, unpublished data). The shellfish samples were harvested from approved waters in 20 coastal states (all coastal states except Alaska and New Hampshire). The results of that survey are presented in Table 4.
Table 4. Results of the 1985-86 FDA shellfish survey for cadmium.
Mean cadmium level* Range Species (
Clam, hardshell 0.085 0.018-0.14 Clam, softshell 0.049 0.044-0.058 Oyster, Eastern 0.51 0.25-1.12 Oyster, Pacific 1.2 0.83-1.4 Clams, overall 0.067 Oysters, overall 0.86 * Wet weight basis
In 1978, the National Marine Fisheries Service (NMFS) published the results of a survey on trace elements in fish (Hall et al., 1978). The cadmium levels in several species of shellfish were reported. The results are presented in Table 5.
Table 5. Results of the NMFS survey of trace elements in the fishery resource for selected shellfish.
Range of mean cadmium level(1),(2) Species (
Clam, hardshell 0.2-0.3 Clam, softshell 0.2-0.3 Oyster, Eastern 0.9-1.0 Oyster, Pacific 1.0-2.0 Average of the range of mean 0.6-0.9 cadmium levels for molluscs Crab, blue, body/claw 0.1-0.2 Crab, dungeness, body/claw 0.1-0.2 Lobster, American, tail 0.4-0.5 Lobster, spiny, Atlantic, tail <0.1 Lobster, spiny, Pacific, tail 0.2-0.3 Shrimp, ocean 0.1-0.2 Shrimp, pink (northern) 0.1-0.2 Average of the range of mean 0.2-0.3 cadmium level for crustaceans (1) Wet weight basis (2) Shellfish from a single survey site formed a sample. Cadmium content was averaged for each sample. Each species was sampled at many sites. This table reports the range of the mean cadmium levels that encompassed all samples.
Cadmium levels reported in the NMFS survey are slightly higher than those in the FDA survey. The significance of this result is not entirely clear, and no clear explanation is available. In general, greater numbers of each species were sampled in the NMFS survey. The FDA survey data, however, were gathered seven years or more after the NMFS survey. The NMFS is beginning a resurvey of trace metals in marine organisms and the results of this survey may delineate any trend in cadmium contamination in marine organisms. Until such data are available to corroborate the FDA study, we believe it is prudent to use the NMFS data to estimate consumer exposure.
3. Cadmium Exposure from Shellfish
Using information on chronic shellfish consumption and typical
levels of cadmium in shellfish, it is possible to estimate
cadmium intake on a chronic basis for consumers of shellfish.
According to the MRCA survey, only 13% of the population eat
crustacean shellfish, and only 4.8% of the population eat
molluscan bivalves. Assuming that mean cadmium levels range from
0.6 g/g (ppm) to 0.9 g/g for molluscan bivalves and from 0.2
g/g to 0.3 g/g for crustacean shellfish, consumer exposures
(for eaters only) are presented in Tables 6 and 7, below.
Table 6. Molluscan bivalves - chronic cadmium intake for specified levels of contamination,
Contam. at 0.6 ppm Contam. at 0.9 ppm Age Group,Yrs. Mean 90th Mean 90th Percentile Percentile
2+ (all ages) 6 9 9 14 (male/female) 2-5 2 5* 4 7* (male/female) 18-44 7 11 11 16 (male/female) * Estimated value. Reliable data are not available in the MRCA survey. The 90th percentile value is estimated to be twice the mean (WHO, 1983).
Table 7. Crustacean shellfish - chronic cadmium intake for specified levels of contamination,
Contam. at 0.2 ppm Contam. at 0.3 ppm Age Group, Yrs. Mean 90th Mean 90th Percentile Percentile
2+ (all ages) 2 3 3 5 (male/female) 2-5 1 2 2 3 (male/female) 18-44 2 4 3 6 (male/female)
4. Background and Relative Source Contribution to Cadmium Exposure
4.1 Diet
Data from the FDA Total Diet Study (TDS) (7-year summary, 4/82 -
2/89) (E. Gunderson, FDA, Division of Contaminants Chemistry,
unpublished data) (which does not include shellfish) suggest that
the mean lifetime exposure to total cadmium from all food
(excluding shellfish) is 10 g/person/d (averaging male and
female lifetime total exposures). The major sources of cadmium
in the diet are green leafy vegetables, potatoes, liver, and
milk. The four seafood categories, cod/haddock filets, shrimp,
fish sticks, and tuna account for less than 2% of the total
exposure, suggesting that approximately 10 g/person/d is an
appropriate background exposure to cadmium in the diet.
A Canadian group examined dietary intake of cadmium in their
study of 24 individuals in 5 cities (Dabbeka et al., 1987)
Cadmium intake averaged 13.8 g/person/d, comparable to the
FDA TDS result. Another total diet study of 110 individuals
conducted by Dutch researchers found an average daily cadmium
intake of 10 g/p/d (Ellen, 1990).
Environmental exposure to cadmium (air, dust, and water) does not contribute significantly to background exposure except in the immediate vicinity of a smelting operation (Friberg, 1976). These sources of exposure will be examined in more detail below.
EPA data are available on the relative contributions from these sources. Additional data have been taken from the Agency for Toxic Substances and Disease Registry's (ATSDR) toxicological profile for cadmium (ATSDR/TP-88/08, 1989). None of the environmental sources contribute to a typical (non-smoking) adult's exposure to cadmium. The contribution of cigarette smoke to cadmium exposure will be considered below.
4.2 Water
Konz and Walker (1979) reported that cadmium levels in drinking
water do not exceed 1 g/L. A Canadian group has reported an
average of 0.5 g/L in drinking water (Meranger et al., 1981).
The current EPA maximum contaminant level (MCL) for cadmium in
drinking water is 5 g/L (EPA, January 30, 1991). In soft
water systems with low pH (5-6), cadmium can be dissolved from
water lines or soft solder, which results in elevated cadmium
levels. Cadmium leaching from waste landfills can also cause
drinking water levels to become elevated. A survey of 1063
groundwater sites in New Jersey revealed a median cadmium level
of 1 ppb (g/L), with a high of 405 ppb (Page, 1981). The
exposure from consumption of drinking water with a cadmium level
of 1 g/L is 1.2 g/day (1193 ml water/day, see above).
This intake is accounted for in the FDA-TDS (see discussion
above).
4.3 Air
Elinder (1985) has reported that cadmium levels in urban air are
typically in the range of 5 to 40 ng/m3. He states that these
levels are higher than those found in rural areas (1-5 ng/m3),
but are much lower than those found near active lead or zinc
smelters (300-700 ng/m3). Using the middle of the urban range
for cadmium levels in air (25 ng/m3) we estimate the
contribution to background cadmium exposure to be 0.5 g/day
(20 m(3) air x 25 ng/m3).
4.4 Soil
A typical soil level for cadmium is 260 ppb (Carey 1978). Near a source of contamination, such as a zinc smelter, levels of up to 72 ppm cadmium (at a distance of 1 km) have been found. Uptake of soil cadmium by plants {likely to cause the greatest human exposure, see ATSDR/TP-88/08 (1989)} would be accounted for in the dietary contribution to cadmium exposure. Using the 260 ppb as a typical level, an adult's daily ingestion of 1 mg of soil (see FDA Docket No. 89N-0014, RIN 0905-AC91, 11-30-89, discussion above) gives a background contribution for cadmium of 0.26 ng/day.
4.5 Smoking
The concentration of cadmium in cigarette tobacco is about 1 to 2
g/g. About 20 to 50% of the cadmium in inhaled smoke (10 to
20% of total smoke) is absorbed. An individual smoking one pack
of cigarettes per day might absorb from 1 to 3 g cadmium per
day.
Cadmium exposure resulting from smoking cigarettes is
approximately 10 g/day. The amount of cadmium absorbed from
smoking is approximately equal to the amount absorbed from the
diet. Direct measurement of cadmium levels in body tissues
confirms that smoking roughly doubles cadmium body burden above
levels observed with individuals not smoking (ATSDR/TP-88/08,
1989). Background cadmium exposure for smokers is approximately
10 g/day higher than for non-smokers (or approximately
20 g/p/d).
The background exposures estimated above are mean values meant for those persons not living near sources of contamination. The background exposures estimated for those living or working near high concentration sources of the contaminants would have to be evaluated from information specific to those sites.
5. Select Subpopulations
The preceding exposure estimates for cadmium intake from shellfish consumption are based on nationally representative food consumption surveys. These surveys may not be suitable for estimating exposures to particular subpopulations or individuals residing in specific regions of the country. State or local organizations will want to tailor estimates to their specific needs.
In addition to the nationwide food consumption surveys mentioned previously {Market Research Corporation of America (MRCA) 14-day Survey; USDA 3-Day National Food Consumption Survey (USDA-NFCS}, the National Purchase Diary (NPD) survey presents a 14-day survey covering the continental United States.
Several other food consumption databases are also available for use in preparing estimates of exposure. Although none have the national character of the MRCA, NPD survey, or USDA-NFCS, they do address either the consumption of specific types of food (e.g. fish, shellfish), or they reflect the consumption patterns and habits of regional areas or of specific groups (e.g., fishermen). Some available databases are listed, along with selected shellfish consumption values, are listed in Table 8, below.
Table 8: Shellfish Consumption
Seafood Consumption Level Population Source of the Data Category (g/day) All 5 (availability(a)) Entire U.S. NMFS "Fisheries of the U.S." Shellfish Series (1986)(b) 5 (average) Persons Earning NMFS (1981)(c) More than $15,000 per Year 9 (average) Shellfish-Eaters 1977-1978 Menu Census(d) 16 (90th percentile) Shellfish-Eaters 1977-1978 Menu Census(d) 30 (availability(a)) Shellfish-Eaters NMFS "Fisheries of the U.S." Series (1986)(b) Clams 1 (average) New Englanders NMFS (1981)(c) 22 (95th percentile) Texans 1973-1974 Tuna Institute Survey(e) Oysters 0.5 (average) Persons Earning NMFS (1981)(c) more than $15,000 per year 21 (95th percentile) Californians 1973-1974 Tuna Institute Survey(e) (a) Total availability of edible shellfish "meat" (excluding bones, viscera, shells), fresh, frozen and canned. (b) C. Lewis, FDA, in memo to I. Boyer, FDA, "Estimating a Level of Concern for Cadmium in Shellfish," 10-26-88. (c) Hu, T.-W., (1985). (d) Market Research Corporation of America (MRCA) as reported by C. Lewis, FDA, in memo to I. Boyer, FDA, "Estimating a Level of Concern for Cadmium in Shellfish," 10-26-88. (e) Tuna Research Foundation (1975), Seafood Consumption Study, National Purchase Diary Panel, Inc., Schaumburg, IL.
It is important to note that the level of consumption, and thus the level of contaminant intake, varies from survey to survey. The variation is controlled by several factors, among which are:
Finally, we note that in some circumstances it may be difficult or impossible to find a survey that adequately addresses a particular public health problem. In this case, the best choice may be to initiate a survey that will be specifically designed to address the question.
Cadmium ingestion by animals and humans has been found to result in a variety of toxic effects (e.g., hepatic, bone, and teratogenic). These effects generally occur at exposure levels that far exceed cadmium exposure levels occurring in the diet. The most critical effect relevant to dietary exposure is that which occurs in the kidneys. Impaired renal function can result from long-term oral cadmium exposure in humans and laboratory animals (Task Group on Metal Toxicity, 1976). Some aspects of the mechanism of this effect have been well documented (Friberg et al., 1984), and a brief description follows.
Absorbed cadmium is transported to the liver and stimulates the synthesis of metallothionein in hepatocytes. Part of the cadmium in the plasma is bound to metallothionein and the cadmium-metallothionein complex is transported to the kidneys (Nordberg, 1978; Cherian and Shaikh, 1975; Shaikh and Hirayama, 1979b; Nordberg et al., 1982). Metallothionein and the cadmium- metallothionein complex are both freely filtered from the plasma through the glomeruli and then almost completely reabsorbed from the tubular fluid into the tubular cells in normally functioning kidneys (Foulkes, 1978; Nomiyama and Foulkes, 1977; Nordberg and Nordberg, 1975). The reabsorption is mediated by pinocytic vesicles which transport the cadmium-metallothionein complex, and other filterable low molecular weight proteins and into the cytoplasm of the proximal tubular cells (Squibb et al., 1979; Strober and Waldman, 1974). Thus, cadmium accumulates primarily in the proximal tubules of the renal cortex during long-term chronic exposure. Accordingly, the ratio between cadmium in the renal cortex and the medulla is about 2:1 (Anke et al., 1979; Geldmacher et al., 1968; Syversen et al., 1976).
The metallothionein to which the cadmium is bound is continuously catabolized within the lysosomes of the proximal tubular cells (Cherian and Shaikh, 1975; Shaikh, 1982; Webb and Etienne, 1977; Cherian et al., 1976a; Fowler and Nordberg, 1978; Squibb et al., 1979, Squibb and Fowler, 1984). The released cadmium stimulates metallothionein synthesis in the tubular cells and the cadmium binds to the newly synthesized metallothionein. Thus, continuous synthesis of metallothionein is necessary for the continued sequestration of the cadmium ions released from catabolized metallothionein (Nordberg, 1978; Ridlington et al., 1981; Shaikh, 1982).
However, the capacity of renal tubular cells to produce metallothionein is limited (Elinder, 1979; Iwao et al., 1983a, 1983b). Thus, non-metallothionein-bound intracellular cadmium increases when the total cadmium concentration exceeds the capacity of the proximal tubular cell to synthesize metallothionein. Cadmium may then become available for interacting with other cellular macromolecules, such as the zinc-dependent metalloenzymes, to disrupt tubular cell function (Piscator, 1964; Nordberg et al., 1971; Nordberg et al., 1982; Fowler and Nordberg, 1978; Squibb et al. 1979; Squibb et al., 1982, 1984).
The first sign of renal damage due to cadmium toxicity is decreased proximal tubule reabsorption (Butler and Flynn, 1961; Butler et al., 1962; Piscator, 1962a; Kazantzis, 1963). The resultant proteinuria is characterized by a relative increase in the excretion of low molecular weight proteins, including metallothionein, B2-microglobulin, immune globin chains, and enzymes such as muraminidase and ribonuclease, (Piscator, 1966a,b). The cadmium-induced tubular proteinuria appears to be irreversible (Kjellstrom, 1985). Furthermore, the tubular cells are destroyed after more severe cadmium-induced damage, and the cell contents are then excreted into the urine (Takebayashi, 1980; Bonnell, 1955).
The half-life of cadmium in the kidneys has been estimated to be between 14 and 38 years in human beings (Tsuchiya et al., 1972; Kjellstrom, 1971). Accordingly, cadmium from long-term low-level exposure continues to accumulate in the kidney unless tubular dysfunction develops. In addition, urinary excretion of cadmium increases with age in parallel to the increasing body and kidney burdens as long as normal renal function remains (Elinder et al., 1978; Kjellstrom, 1977; Nowaga et al, 1977). However, subsequent to renal damage excretion of cadmium in the urine increases substantially, and the kidney cadmium concentration decreases.
Total cadmium concentration in the kidney cortex has been
proposed as the best available measure of organ dose until severe
kidney damage occurs (Kjellstrom, 1985). Accordingly, most
animal studies demonstrate that a total cortex cadmium
concentration of 100-300 g/g is associated with renal tubular
damage including proteinuria (Nomiyama et al., 1982b; Suzuki,
1974; Bernard et al., 1981a; Piscator and Larson, 1972; Tohyama
et al., 1981a). For example, Tohyama et al. (1987) recently
reported that as the cadmium concentration in the kidneys of rats
exposed to CdCl(2) by subcutaneous injection increased from 10 to
100 g/g, the urinary levels of metallothionein, cadmium,
copper and zinc increased gradually. These measures were sharply
elevated when the renal cadmium concentration exceeded 100 mg/kg.
The results suggest that the critical concentration in rats lies
between 100 and 200 mg/kg. Furthermore, these researchers
suggest that the critical concentration may be set at lower than
100 mg/kg if smaller changes in the excretion of metallothionein
and alkaline phosphatase reflect cadmium toxicity.
In vivo neutron activation analysis has been used to determine
the kidney dose-response relationship for cadmium-induced
effects in human beings (Roels et al., 1981 a,b; Ellis et al.,
1981). The method measures the amount of cadmium in whole
kidney, and estimates of the kidney cortex concentration from
these data depend on assumptions of average kidney weight and a
conversion factor representing the ratio between cortex and whole
kidney cadmium concentration. Friberg and his coworkers (Friberg
et al., 1971; Kjellstrom et al., 1971) introduced the constant
1.5 as the conversion factor based on the limited data then
available. More recently, Svartengren et al. (1986) used atomic
absorption methodology to measure the cadmium concentration in
the kidneys of twenty 30-59 year old male victims of sudden and
unexpected deaths. The whole kidney cadmium concentrations in
this study ranged from 2.8 to 39 g/g wet weight. The mean ratio
between cadmium in the cortex and cadmium in the whole kidney was
1.30 (median = 1.28) when the ratios were calculated for each
kidney, and 1.28 when the mean cortex cadmium concentration was
divided by the mean whole kidney cadmium concentration (median =
1.21). The results demonstrate that the factor for estimating
the kidney cortex cadmium concentration from measures of whole
kidney concentration lies between 1.21 and 1.30. Accordingly,
the authors suggest a conversion factor of 1.25 rather than 1.5.
Estimates of the critical cortex cadmium concentration in humans
range from 180 to 344 g/g, based on in vivo neutron
activation measurements and the 1.25 conversion factor (Roels et
al., 1981 a,b; Ellis et al., 1981; Kjellstrom et al., 1984).
The criteria used for setting these critical concentrations vary. In
some instances, estimates have been based on the cortex cadmium
concentration at which the kidney cadmium content begins to
decrease ("inflection point") and the liver cadmium content
continues to increase. In other instances, they were related to
estimates of the kidney cortex cadmium concentration
corresponding to the liver cadmium concentration at which a
minimal incidence of renal dysfunction (elevated B2-microglobulin
excretion) is observed. A comparative analysis of the various
criteria was presented by Kjellstrom et al. (1984). These
authors estimated that the cortex concentration at which renal
damage occurs in 50% of a population of cadmium workers ranges
between 250 and 267 g/g. Furthermore, the concentration at
which 10% of the workers exhibit renal damage ranges from 180 to
220 g/g. Accordingly, Roels et al. (1983) estimated that 10%
of the workers will exhibit renal dysfunction at 180 g/g,
using 1.25 rather than 1.5 as the conversion factor.
However, the critical renal cortex and the critical urinary
cadmium concentrations estimated from studies on male cadmium
workers may not be applicable to other population. For example,
Lauwerys and his coworkers (Lauwerys et al., 1974; Roels et al.,
1979) demonstrated that a correlation exists between urinary
cadmium levels and renal cortical cadmium concentrations in
workers with normal renal function exposed to cadmium. Further,
they showed that an association exists between elevated urinary
cadmium andB122-microglobinuria. The workers with proteinuria
exhibited a mean urinary cadmium level of 13.9 g/g creatinine
(median = 8.8 g/g) compared to 6.3 g/g (median = 3.5 g/g) in
the workers with normal kidney function. These authors estimated
that the critical level of urinary cadmium in the workers is
between 10 and 15 g Cd/g creatinine. Similarly, proteinuria was
correlated with urinary cadmium in several populations of aged
women (Lauwerys et al., 1980; Roels et al, 1981). The women who
had lived in cadmium-polluted areas exhibited a higher cadmium
body burden, as reflected by a mean urinary cadmium level of 2.3
g/g creatinine, compared with 1.1 g/g in the control population
(calculated from the data presented in the reports). These
results show that the critical urinary cadmium concentration is
much lower in elderly persons than in middle-aged male workers.
Furthermore, the study demonstrates that cadmium exposure may
exacerbate the age-related decline in renal function in non-occupationally
exposed populations.
In summary, the available human and animal data are consistent
with the prediction that sensitive individuals, representing 10%
or more of the population, will exhibit renal tubular damage
manifested by low molecular weight proteinuria at renal cortex
cadmium concentrations ranging between 180 and 220 g/g. These
values represent the best estimates possible with the information
currently available.
Epidemiological data indicate that renal dysfunction (500-700 g
B2-microglobulin per liter of urine) will occur in 50% of a
non-occupationally exposed population (average body weight = 70 kg)
after 50 years of exposure averaging 562 g Cd/day. The average
intakes corresponding to 10% and 5% response rates are 156 and
108 g/day respectively. The 5% response rate is the lowest
level at which empirical data are available. Calculations using
a kinetic model (Kjellstrom and Nordberg, 1978; Nordberg and
Kjellstrom, 1979) derived from distributions of estimated
critical concentrations in cadmium-exposed populations reveal a
similar dose-response relationship. For example, the model
predicts that 11% of a population with an average intake of 200
g Cd/day will exceed their individual critical kidney cortex
cadmium concentration at age 45, assuming that the PCC-10
(population critical concentration for 10% response rate) is 180
g/g and the PCC-50 is 250 g/g. An extrapolation of the
dose-response relationship from the model reveals that tubular
proteinuria may develop in 1% of the population after 45 years of
exposure to 55 g Cd/day (population average) in food
(Kjellstrom, 1984, Chapter 13, this book). This value is nearly
equivalent to the WHO/FAO provisional tolerable weekly intake of
7 g Cd/kg for individuals (WHO, 1989) (or about 60 g/day for
a 60 kg person). However, the average population intake must be
below 55 g/day to maintain maximal individual intakes below
60 g/day. A tolerable daily intake of cadmium of
55 g/person/day is suggested in this document.
The calculations discussed above assumed that gastrointestinal absorption of cadmium averages 5% (Rahola et al., 1972; McLellan et al., 1978). Thus, one important consideration is that lower average daily cadmium intakes will produce the critical cortex concentration in populations in which the average cadmium absorption is higher due, for example, to low iron or calcium uptake (Nordberg et al., 1985b; Flanagan et al., 1978).
The following section illustrates how Levels of Concern, either permitted amounts of chronic shellfish consumption or permitted levels of contamination, can be determined using information on the tolerable daily intake for cadmium. For the purpose of this illustration, it is assumed that total cadmium exposure is derived solely from shellfish. This approach leads to estimates of the maximum permitted levels of either shellfish intake or levels of cadmium contamination in the shellfish. If other sources of cadmium exposure are to be considered (e.g., relative source contribution including other dietary sources of cadmium), then corresponding adjustments in the levels of concern will need to be made.
It is recommended that the molluscan bivalves and crustacean shellfish intakes be considered separately in the preparation of guidance levels. As can be seen from data presented in the previous section, these shellfish have different contaminant levels. Therefore, use of a total shellfish intake figure when deriving a guidance level for cadmium may lead to bias against one or the other types of shellfish.
The following equations illustrate how the tolerable daily intake
of cadmium (55 g/person/day) can be combined with information
on either shellfish consumption or cadmium levels to estimate the
corresponding levels of concern of either shellfish contamination
or shellfish intake.
Total Cd Level of Concern =
Tolerable Daily Intake of Cd / Daily Intake of Shellfish
As an example, the Total Cd Level of Concern is estimated for individuals in the 2+ year age group consuming molluscan bivalves on a chronic basis at the 90th percentile level (15 g/person/day, see Table 2).
Total Cd Level of Concern = {55 g/p/d / 15 g/p/d} = 3.7 g/g
For molluscan bivalves with Cd levels corresponding to the highest mean concentration reported in the 1978 NMFS survey (see Table 5), the corresponding molluscan bivalve consumption level of concern is calculated as follows:
Consumption Level of Concern = 55
The following tables present a number of plausible levels of concern, either consumption or concentration, that could be used in the assessment of the potential impact of cadmium on human health through exposure from shellfish. For reference, the following values should be compared with shellfish intake and Cd contamination figures presented in Section IV.
Table 9. Consumption Levels of Concern for Cadmium (g/p/d)*
Molluscan Bivalves 28Crustaceans 110
* Derived from the tolerable daily intake for Cd and the highest mean concentration for total cadmium (see Table 5) reported in the 1978 NMFS survey.
Table 10. Cadmium Levels of Concern in Molluscan Bivalves (
Age Group Mean 90th Percentile
2+ years (all ages) 6 4 18-44 years 5 3 (male/female) * Derived from the tolerable daily intake for cadmium and intake figures for molluscan bivalves presented in Table 2. Since cadmium toxicity is expressed only after chronic exposure, separate figures for the age category 2-5 years are not warranted.Table 11. Cadmium Levels of Concern for Crustacean Shellfish (
Age Group Mean 90th Percentile
2+ years (all ages) 6 3 18-44 years 6 3 (male/female) * Derived from the tolerable daily intake for cadmium and intake figures for crustacean shellfish presented in Table 3. Since cadmium toxicity is expressed only after chronic exposure, separate figures for the age category 2-5 years are not warranted.
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This Guidance document represented current agency thinking in regards to the available science at the time it was issued. It no longer represents the current state of science and is presented here for the historical record only.