g/person/day.
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 It no longer represents the current state of science and is presented here for the historical record only.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 12
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. Nickel Concentrations in Shellfish
3. Nickel Exposure from Shellfish
4. Background and Relative Source Contribution to Nickel Exposure
4.1 Diet
4.2 Air
4.3 Water
4.4 Soil
4.5 Cigarettes
4.6 Summary
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 nickel 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 nickel 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.
Nickel is widely distributed in the environment. Nickel concentrations in the
environment are related to the consumption of fossil fuels, emissions from
nickel mining and refining, and by the incineration of wastes. Sources of
human exposure are air, water, food, and tobacco with food representing the
major route of uptake for the general public (cigarette smoke is second).
Nickel is widely distributed in foods with the highest concentrations
occurring in cereals, nuts, cocoa, and soya products. Data from the FDA Total
Diet Study (which does not include shellfish) suggest that the mean lifetime
exposure to nickel from all food (excluding shellfish) is 120
g/person/day.
Most nickel salts ingested orally are excreted rather than absorbed. The
half-life for orally ingested nickel is about 11 hours. The normal body
burden of nickel averages about 7.3 g/kg body weight. The highest
concentrations are found in bone, lung, kidney, and liver. The toxicity of
nickel is classified into four separate categories: (1) allergy; (2) cancer
and (3) non-malignant respiratory disorders (both of which are almost
exclusively limited to industrial settings); and (4) iatrogenic poisoning.
The World Health Organization has not set a tolerable intake level for nickel,
but based on EPA's oral reference dose of 20 g/kg/day, a provisional
maximum
tolerable daily intake of nickel of 1.2 mg/person/day can be estimated.
However, a tolerable daily intake of only 50 g/person/day is estimated for
individuals who may experience dermatitis as a result of acute oral exposures
to nickel.
Surveys of contaminants in shellfish conducted by FDA and the National Marine
Fisheries Service have found mean nickel levels ranging from 0.2 ppm up to 2.2
ppm. FDA has combined these survey results with nationally representative
shellfish consumption information to estimate the range of nickel 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 nickel levels of 0.9 ppm, nickel intake will average 14
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 nickel levels of 0.4
ppm, nickel intake will average 7 g/person/day.
Local patterns of shellfish consumption and/or the levels of nickel
contamination may vary from national averages. Hence, nickel exposures from
shellfish in particular regions may also vary from values estimated using
national figures. In order to decide whether local nickel exposure levels are
of concern, it is suggested that the maximum tolerable daily intake for nickel
(for the general population, 1200 g/person/day) be used to calculate
Levels of Concern, either maximum permitted amounts of chronic
shellfish consumption or maximum permitted levels of nickel 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 nickel exposure is derived solely from shellfish, it is calculated that the nickel level of concern for individuals consuming molluscan bivalves on a chronic basis at the 90th percentile average among eaters (15g/person/day) would be 80 ppm. The corresponding consumption level of concern for individuals consuming molluscan bivalves with nickel levels equivalent to the highest average found in one of the national surveys (2 ppm) is 600 g/person/day.
If other sources of nickel exposure are to be considered (e.g., relative
source contribution including other dietary sources of nickel), then
corresponding adjustments in the levels of concern will need to be made.
Although a similar approach could be taken using the tolerable daily intake
for individuals who are acutely sensitive to nickel (in this case, however,
acute shellfish consumption figures would need to be considered), it may not
be appropriate to do so since the background (i.e., non-shellfish) exposure to
nickel (120 g/day) exceeds the tolerable daily intake for sensitive
individuals (50 g/d).
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.
Nickel (Ni) is widely distributed in the environment in two oxidation states. The most prevalent oxidation states of nickel are 0 as in the nickel metal and its alloys and +2 in common water-soluble and insoluble compounds. The most toxic form of Ni, encountered mostly in the workplace, is nickel carbonyl. The predominant industrial use of nickel is as a constituent of more than 3,000 metal alloys, which are principally used in the production of stainless steels by the automotive industries, in cooking utensils, in corrosion-resistant equipment, in food processing, in Ni-Cd batteries, in pigments for paints and ceramics, and in magnetic and computer components. It is also used in electroplating, in the manufacture of magnetic tapes, nickel-chrome resistance wire, in jewelry and coinage, as a catalyst for the hydrogenation of fuels and oils in catalytic gasification of coal, and in surgical and dental protheses. Nickel carbonyl is the most important organic lipid-soluble nickel compound and is formed as an intermediate in the Mond process for nickel refining. It is also formed in processes that use nickel catalysts and has been found in trace quantities in cigarette smoke and in the atmosphere near heavy traffic intersections.
The nickel concentrations in the environment are related to the consumption of fossil fuels by stationary and mobile power sources, from the emissions of nickel mining and refining, and by the incineration of wastes. Iatrogenic sources of nickel include nickel-containing prostheses, contaminated intravenous fluids, and medications; and extracorporeal hemodialysis. Occupational exposures to high levels of nickel may result from nickel mining, refining, and smelting, electroplating, production and use of nickel catalysts, fabrication of parts and structures by welding, manufacturing of Ni-Cd batteries, nickel molds in glass bottles, and recycling or disposing of nickel-containing products.
The levels of nickel in the atmosphere range from 1-20 ng/m3 in non-urban
areas and 10-60 ng/m3 in urban areas. The average level of exposure via
inhalation is 1 g/day. Nickel levels in sea water are 0.1-0.5 g/L.
Drinking water and surface water concentrations average less than 20 g/L
and 15-20 g/L, respectively. The total dietary nickel intake varies
greatly with the amounts and properties of foods of animal and plant origin,
and with the amounts of refined and processed foods in the diet. The average
daily dietary intake (excluding shellfish) for an adult person is
approximately 120 g/person/day.
For the general population the major source of nickel is the diet. Nickel is widely distributed in foods, with the highest concentrations occurring in cereals, nuts, cocoa, and soya products. The concentration of Ni in shellfish varies. Levels ranging from 0.2-2.2 ppm (wet weight) have been determined in hardshell clams and 0.5-1.9 ppm in eastern oysters.
The major route of exposure to nickel is by ingestion. Most nickel salts
taken orally by humans and animals are excreted rather than absorbed. The
rate of nickel absorption from the gastrointestinal (GI) tract is dependent
upon the chemical form of the nickel. While soluble nickel compounds are
better absorbed than relatively insoluble ones, the contribution of poorly
soluble compounds to total absorption may be more significant because they
become more soluble once they are in the acidic gastric fluids. Once nickel
is in the blood, the transport of Ni (II) in plasma is mediated by binding of
the nickel to albumin. A major fraction of plasma nickel is bound to
nickelplasmin, an alpha-macroglobulin. The normal body burden for nickel
averages about 7.3 g/kg body weight. The highest concentrations are found
in bone followed by lung, kidney, and liver. The half-life for orally
ingested nickel is approximately 11 hours. Cigarette smoke accounts for the
second major route of nickel exposure. Cigarettes contain 1-3 g of
nickel,
10-20% of which is released into the smoke stream. Thus a one pack/day smoker
is exposed to an additional 2-12 g nickel/day.
The toxicity of nickel is classified into four separate categories: (1)
allergy, a hypersensitivity to nickel manifested by contact dermatitis; (2)
cancer, almost exclusively limited to refinery workers who inhale nickel; (3)
non-malignant respiratory disorders, most frequently occurring in industrial
settings due to the inhalation of nickel carbonyl; and (4) iatrogenic
poisoning in patients undergoing extracorporeal hemodialysis, corrosion of
stainless steel prostheses, and nickel-contaminated medication or medication
such as disulfiram that causes increased nickel concentration in the blood.
The World Health Organization has not set a tolerable intake level (TIL) for
nickel (Private Communication 7). Based on EPA's oral reference dose (RfD) of
20 g/kg/day (EPA, 1985), a provisional maximum tolerable daily intake of
1.2 mg Ni/day for a 60 kg individual has been suggested. However, a tolerable
daily intake of only 50 g is suggested for hypersensitive individuals who
may
experience dermatitis as a result of acute exposures to nickel.
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 acute and chronic shellfish intake as well as estimates of nickel exposures resulting from acute and chronic shellfish consumption. In addition, estimates of nickel 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, 1982-1987) (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
alculation. 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).
The mean and 90th percentile intakes of food from the 14-day MRCA (MRCA, 1988) survey are typically used to model probable chronic, or long-term, exposure to foods, food additives, or contaminants. Acute, or single exposures can be equated to the standard portion sizes of the USDA-NFCS (Pao et al., 1982). For those consuming molluscan bivalves and crustaceans, the acute intakes are presented in Table 4.
Table 4. Acute intake of molluscan bivalves and crustaceans,
grams/person/day, for eaters-only.
Molluscan Bivalves Crustaceans
Age Group Mean 90th Mean 90th
Percentile Percentile
Adults 117 227 67 135
Children 70 113 31 62*
(3-5 years)
* Estimated value. Data are not available in the
USDA-NFCS survey. The 90th percentile value is
estimated to be twice the mean (WHO, 1983).
2. Nickel Concentrations in Shellfish
In 1985-86 the FDA surveyed the levels of nickel 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 were harvested from approved waters in 20 coastal states (all coastal states except Alaska and New Hampshire), although not all species were sampled in all states. The results of that survey are presented in Table 5.
Table 5. Results of the 1985-86 FDA shellfish survey for nickel.
Sample Mean nickel level(1) Range Species Size (
Clam, hardshell 67 1.3 0.17-2.2 Clam, softshell 59 0.6 0.17-0.93 Oyster, Eastern 100 0.77 0-1.9 Oyster, Pacific 40 0.23 0.043-0.29 Clams, overall 0.95 Oysters, overall 0.50 (1) 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 levels of nickel in several species of shellfish were reported. The results are summarized in Table 6.
Table 6. Results of the NMFS survey of trace elements in the
fishery resource for selected shellfish.
Range of mean
Sample nickel levels 1,2
Species Size (g/g)
Clam, hardshell 140 1.0-2.0
Clam, softshell 19 0.5-0.6
Oyster, Eastern 151 0.5-0.6
Oyster, Pacific 69 0.3-0.4
Average of the range of mean 0.6-0.9
nickel levels for
molluscan bivalves
Crab, blue, body/claw 53 0.4-0.5
Crab, dungeness, body/claw 7 0.3-0.4
Lobster, American, tail 2 0.3-0.4
Lobster, spiny, Atlantic, tail 40 0.3-0.4
Lobster, spiny, Pacific, tail 5 0.3-0.4
Shrimp, ocean 10 0.2-0.3
Shrimp, pink (northern) 64 0.3-0.4
Average of the range of mean 0.3-0.4
nickel levels for
crustaceans
(1) Wet weight basis.
(2) Shellfish from a single survey site formed a sample.
Nickel content was averaged for each sample. Each species
was sampled at many sites. This table reports the range of
the mean nickel levels that encompassed all samples.
The analytical results from the FDA and the NMFS surveys are in close agreement for clams and oysters. Crustacean shellfish were not sampled in the FDA survey, but were sampled by the NMFS. NMFS concentration range values will be used for the exposure calculations presented below.
3. Nickel Exposure from Shellfish
Using information on chronic shellfish consumption and typical levels of
nickel in shellfish, it is possible to estimate nickel intake on a chronic
basis for consumers of shellfish. According to the MRCA survey (MRCA, 1988)
only 13% of the population eat crustacean shellfish, and only 4.8% of the
population eat molluscan bivalves. Assuming that mean nickel levels range
from 0.6 g/g (ppm) - 0.9 g/g for molluscan shellfish and from
0.3 g/g - 0.4 g/g for crustacean bivalves, consumer exposures (for
eaters-only) are presented in Tables 7 and 8, below.
Table 7. Molluscan bivalves - chronic nickel intake for
specified levels of contamination, g/person/day
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 4* 4 8*
(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 8. Crustacean shellfish - chronic nickel intake for
specified levels of contamination, g/person/day
Contam. at 0.3 ppm Contam. at 0.4 ppm
Age Group, Yrs. Mean 90th Mean 90th
Percentile Percentile
2+ (all ages) 3 5 4 7
(male/female)
2-5 2 3 2 4
(male/female)
18-44 3 6 4 8
(male/female)
Acute exposure to nickel from consumption of a shellfish meal is estimated, for the range of nickel concentrations reported by NMFS, in Tables 9 and 10, below.
Table 9. Molluscan shellfish - acute nickel intake for
specified levels of contamination, g/person/day
Contam at 0.6 ppm Contam at 0.9 ppm
Age Group Mean 90th Mean 90th
Percentile Percentile
Adults 70 136 105 204
Children 42 68 63 102
(3-5 years)
Table 10. Crustacean shellfish - acute nickel intake for
specified levels of contamination, g/person/day.
Contam. at 0.3 ppm Contam. at 0.4 ppm
Age Group Mean 90th Mean 90th
Percentile Percentile
Adults 20 41 27 54
Children 9 18* 12 24*
(3-5 years)
* Estimated value. Reliable data are not available in the MRCA
survey (MRCA, 1988). The 90th percentile value is estimated
to be twice the mean (WHO, 1983).
4. Background and Relative Source Contribution to Nickel Exposure
Nickel is ubiquitous in the environment (air, dust, and water), albeit at low levels, and does not contribute significantly to background exposure except for those individuals living in the immediate vicinity of nickel-producing facilities. Industrialized urban areas are also likely to have higher levels of nickel in the air and water than rural areas. Nickel in cigarette smoke is the second largest source of nickel exposure (food is first). We shall examine the individual sources below.
4.1 Diet.
Data from the FDA Total Diet Study (1984 Market Basket) (Pennington and Jones,
1987) suggest that the mean lifetime exposure to nickel from all food
(exclusive of shellfish) is 120 g/p/d (averaging male and female lifetime
total exposures). This nickel is distributed throughout the diet, with the
largest contributions to exposure from cereals, nuts, and cocoa products.
4.2 Air.
Nickel levels in ambient air have been reported to be in the range from 1-20
ng/m3 in rural areas and from 10-60 ng/m3 in urban areas
(Sexton et
al. 1980).
Using 50 ng/m3 nickel and EPA's 20 m3/day estimate of
air intake (EPA, 1989),
we estimate 1 g/day nickel exposure from air. Air in heavily
industrialized
urban areas may have nickel levels greater than two times this estimate.
4.3 Water.
It should be noted that the FDA's Total Diet Study (TDS) (Pennington and Jones, 1987) from which our non-seafood food contribution to nickel exposure was derived, includes tapwater as a beverage explicitly in its sample diet, as well as in water used in the preparation of food. Therefore, water's contribution to nickel exposure has been taken into consideration in the food portion of background nickel exposure.
4.4 Soil.
Nickel levels in soil have been reported to range from 5-500 g/g (ppm),
with
typical levels below 50 g/g (Bennett, 1984). The Coalition for Safe
Ceramicware, in its report on lead intake (FDA, 1989), estimates soil
ingestion for adults of 1 mg/day. The contribution to non-seafood exposure to
nickel will thus be taken as 50 ng/day (50 ppm x 1 mg soil/day).
4.5 Cigarettes.
Cigarettes contain 1-3 g nickel each. Approximately 10-20% of the nickel
is
released into the smoke stream. Therefore, someone smoking one pack of
cigarettes a day could be exposed to 2-12 g nickel/day (ATSDR, 1989)
4.6 Summary
The non-shellfish, background exposure to nickel from the diet and environment
is approximately 120 g/day for those non-smoking individuals not living
near
a source of nickel contamination (e.g., a nickel-producing plant).
Cigarette
smoke (one pack a day) can add up to 12 g nickel/day to background
exposure.
The exposure for those individuals living near sources of nickel contamination
would have to be evaluated on a case-by-case basis reflecting the nature and
extent of the contamination.
5. Select Subpopulations
The preceding exposure estimates for nickel 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, 1988) 14 day Survey; USDA 3-Day National Food Consumption Survey (USDA-NFCS) Pao et al., 1982}, the National Purchase Diary (NPD) survey (TRF, 1975) 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, along with selected shellfish consumption values, are listed in Table 11, below.
Table 11: 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.
Nickel dusts and several water-insoluble nickel compounds, especially the oxide and subsulfide, are carcinogenic in animals after inhalation or parenteral administration (Ottolenghi et al., 1975; IARC, 1976; Sunderman, 1984; Horie et al., 1985). Accordingly, increased incidences of pulmonary and nasal cancers in nickel refinery workers have been attributed to the inhalation of nickel compounds (Sunderman, 1977). However, there is no indication from the available evidence that ingested nickel is carcinogenic in humans or in laboratory animals.
While nickel chloride was not mutagenic in several bacterial assay systems (EPA, 1985), nickel did produce chromosomal aberrations in cultured mammalian cells, and sister chromatid exchanges in both cultured mammalian cells and human lymphocytes (Miyaki et al., 1979; Ciccarelli et al., 1981; Saxholm et al., 1981; Newman et al., 1982; Robison and Costa, 1982). The relevance of these findings to the toxicity of nickel compounds in vivo remains to be determined.
The World Health Organization (WHO) has not yet suggested a tolerable intake level for nickel (Private Communication 7, June 26, 1990).
The EPA's current oral Reference Dose (RfD) for soluble inorganic nickel is 20
g/kg/day. This value was calculated by applying an uncertainty factor of
100 and a modifying factor of 3 to a no observed adverse effect level (NOAEL)
of 5 mg/kg/day obtained in a 2-year rat feeding study (Ambrose et al.,
1976).
Ambrose et al. (1976) studied clinical pathology, ophthalmology, serum
biochemistry, body, and organ weight changes, and performed histopathologic
evaluations of selected organs (heart, kidney, liver). The EPA's modifying
factor of 3 was applied to the NOAEL, in addition to the uncertainty factor of
100, to compensate for the statistical and other inadequacies in the available
reproductive studies (RTI, 1987; Ambrose et al., 1976). A tolerable
daily intake of 1,200 g Ni/day for a 60-kg individual can be suggested on
the basis of the EPA's current RfD (20 g/kg/day x 60 kg = 1,200 g/day).
An additional concern not yet addressed in the EPA's estimate for the RfD for nickel {and the proposed maximum contaminant level (MCL) corresponding to this RfD} is that acute oral nickel ingestion, added to a normal diet, may produce adverse reactions in persons with nickel hypersensitivity. Hypersensitivity to nickel is a common cause of allergic dermatitis in people (Sunderman, 1988). Sensitization due to cutaneous contact with nickel or nickel compounds is observed in 5-13% of various populations exhibiting eczema (NAS, 1975). Furthermore, positive dermal patch tests for nickel were observed in 7-11% of women and 0.2-2% of men from the general population. Nickel hypersensitivity has been attributed to direct cutaneous exposure to stainless steel utensils and other nickel-containing or nickel-plated objects such as coins, watches, jewelry and clothing fasteners (Norseth, 1986; Sunderman, 1988). Nickel hypersensitivity may also cause pulmonary asthma, conjunctivitis, and inflammatory reactions around nickel-containing implants and prostheses (Arvidsson and Bogg, 1959; Sunderman, 1988).
A double-blind study conducted by Gawkroder et al. (1986) showed that
a single 5,600 g oral dose of nickel worsened the skin conditions in all
6 of the subjects challenged with this dose, confirming the results of
Christensen and Moller (1975). Gawkroder et al. (1986) suggest that
oral nickel intake as high as 5,600 g can aggravate the eczematous skin
conditions in nickel-hypersensitive persons.
Kaaber et al. (1978) reported that 17 of 28 patients with chronic
nickel dermatitis exhibited aggravated eczematous reactions after ingesting a
single 2,500 g dose of nickel as nickel sulfate in a tablet. According to
Kaaber and his coauthors, the protocol in this study included a "blind
challenge with tablets of identical appearance ... carried out by giving each
patient a placebo tablet and three days later a tablet containing 2,500 g
nickel sulfate." The patients were photographed 3 days after the ingestion of
each tablet, and the photographs were then evaluated "blindly".
Thus, this study, like that of Gawkroder et al. (1986), appears to be a
double-blind study.
Veien et al. (1983) reported that three patients with positive patch
tests to nickel developed flares at the patch test site after a single oral
dose of 2,500 g nickel. Accordingly, Kaaber et al. (1979) reported
that eczema was
aggravated in 11 nickel-hypersensitive patients ingesting a single dose of
2,500 g nickel. In two of these patients, with particularly long-standing
(10-17 years) hand dermatitis, a single dose of 600 g or 1,250 g
nickel
sulfate was sufficient to produce dizziness and nausea as well as exacerbated
skin conditions.
Furthermore, Cronin et al. (1980) reported that ingestion of a single
dose of 600 g or 2,500 g nickel, administered after an overnight fast,
produced a dose-dependent enhancement of hand eczema in female patients known
to have been sensitized from nickel contact. Of the five women receiving 600
g nickel, one developed erythema, two presented with worsening of hand
eczema, and 3 exhibited flare of the patch test site.
Gawkroder et al. (1986) state
in their introduction that the reports of Cronin et al. (1980),
Kaaber et al., 1979, Veien et al., 1983, and other researchers
were not confirmed by two double-blind studies (Jordan and King, 1979;
Burrows et al., 1981). However, Gawkroder and his colleagues also
mentioned that a subject in one of these double-blind studies (Jordan and
King, 1979) consistently reacted to a 500 g oral nickel challenge.
In summary, one double-blind study showed that a single 2,500 g dose of
orally administered nickel was sufficient to aggravate the chronic nickel
dermatitis in 17 of the 28 patients tested. Other, less reliable studies
suggest that as little as 600 g or 1,250 g of ingested nickel may
exacerbate the skin conditions in patients with long-standing (10-17 years)
nickel hypersensitivity. In one double-blind study (Jordan and King, 1979),
one of the 10 nickel hypersensitive patients tested consistently reacted to a
500 g oral nickel challenge. Thus, oral nickel exposure of as little as
500 g may produce adverse reactions in some nickel hypersensitive persons.
A tolerable intake for nickel of 50 g/day
can be derived by applying an uncertainty factor of 10 to the lowest
observed effect level for dermatitis in hypersensitive individuals.
The following section illustrates how levels of concern,
either permitted amounts of shellfish consumption or permitted levels
of contamination, can be
determined using information on the tolerable daily intake for nickel. The
tolerable daily intake of nickel for the general population(1200 g/person/day)
provides a basis for estimating levels of concern for shellfish
consumed on a chronic basis. The tolerable daily intake for individuals who
are acutely sensitive to nickel (acute intake of 50 g/person/day)
provides a different basis for estimating levels of concern, in this case, for single
servings of shellfish. For the purpose of this illustration, it is
assumed that total nickel exposure is derived solely from shellfish.
This approach leads to estimates of the maximum permitted levels of either
shellfish intake or levels of nickel contamination in the shellfish.
If other sources of nickel exposure are to be considered (e.g.,
relative
source contribution), 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 nickel may lead to bias against one or the other types of shellfish.
The following equations illustrate how the tolerable daily intake for nickel
for the general population (1200 g/p/d) can be combined with information
on
either chronic shellfish consumption or nickel levels in shellfish to estimate
the corresponding levels of concern of either total nickel
contamination
levels or chronic shellfish intake. Although a similar approach could be
taken using the tolerable daily intake for individuals who are acutely
sensitive to nickel, it may not be appropriate to do so since background
(i.e., non-shellfish) exposure to nickel (120 g/person/day) exceeds the
tolerable daily intake (50 g/day) for individuals sensitive to nickel.
Total Ni Level of Concern = {Tolerable Daily Intake} / {Daily intake of Shellfish}
As an example, the Total Ni 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/p/d, see Table 2).
Total Ni Level of Concern = {1200 g/p/d} / {15 g/p/d} = 80 g/g
For molluscan bivalves with nickel levels corresponding to the highest mean concentration reported in the 1978 NMFS survey (see Table 6), the corresponding molluscan bivalve Consumption Level of Concern is calculated as follows:
Consumption Level of Concern = {1200 g/p/d} / {2.0 g/g} = 600 g/p/d
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 nickel on human health through exposure from shellfish. The following values should be compared with shellfish intake and nickel contamination figures presented in Section IV.
Table 9. chronic Consumption Levels of Concern for Nickel
(g/p/d)*
Molluscan bivalves 600
Crustacean shellfish 2400
* Derived from the tolerable daily intake for the general population and the
highest mean concentration for total nickel (see Table 6) reported in
the 1978 NMFS survey.
Table 10. Concentration Levels of Concern for Nickel (g/g)*
Levels of Concern (g/g)*
Mollusks Crustaceans
Age Group Mean 90th Mean 90th
Percentile Percentile
Adults 120 80 130 70
* Derived from the tolerable daily intake for the general population and the
highest mean concentration for total nickel (see Table 6) reported in the
1978 NMFS survey.
Abu-Samra, A., Morris, J. S. and Koirtyohann, S.R.(1975) Anal. Chem. 47:1475.
Adeloju, S.B. and Bond A.M. (1983) Anal. Chim. Acta 148:59.
Agemian, H., Sturtevant, D.P. and Austen, K.D. (1980) Analyst 105:125.
Agemian, H. and Thomson R. (1980) Analyst, 105:902.
Ambrose, A.M., Larson, P.S., Borzelleca, J.F., et al. (1976) J. Food Sci. Technol. 13:181.
ASTM (American Society for Testing and Material) (1986) 11.01, D3559-85, Philadelphia, PA 19103.
APHA (American Public Health Association) (1986) Standard Methods for the Examination of Water and Waste Water, 16th Ed., Washington, DC.
Arvidsson, H. and Bogg, A. (1959) Acta Derm. Venereol. 39:30.
ATSDR/TP-88/19 (Agency for Toxic Substances and Disease Registry) (1989) Under contract No. 68-C8-0004. Prepared by Life Systems Inc. for ATSDR, US Public Health Service and the US Environmental Agency.
Balogh K.V. (1988) Bull. Environ. Contam. Toxicol., 41(6):910.
Barrett, P., Davidowski, L.J., Penaro K.W. and Copeland, T.R. (1978) Anal. Chem., 50: 1021.
Beauchemin, D., McLaren, J.W. and Berman, S.S. (1988) J. Anal. At. Spectrom. 3:775.
Bennett (1984) In Nickel in the Human Environment, IARC Scientific Publications, Lyons, France.
Blust, R., Van der Linden, A., Verheyen, E. and Decleir, W.J. (1988) J. Anal. At. Spectrom. 3:387.
Bond, A.M. and Nagaosa, Y. (1985) Anal. Chim. Acta. 178:197.
Boyer, I.W. and Horwitz, W. (1986) Special Considerations in Trace Element Analysis of Foods and Biological Materials. In Environmental Carcinogens-Selected Methods of Analysis, I. K. O'Neil, P. Schuller and L. Fishbein, Eds., International Agency for Research on Cancer, Lyon, 8: 191.
Breyer P.H. and Gilbert, B.P. (1987) Anal. Chim. Acta. 201:23.
Burguera, M., Burguera, J.L. and Alarcon, O.M. (1986) Anal. Chim. Acta. 179:351.
Chakrabarti, C.L., Wan, C.C. and Li, W.C. (1979) Spectrochim. Acta, 35B:547.
Chisela, F. and Bratter, P. (1986) Anal. Chim. Acta. 188:85.
Christensen, O.B. and Moller, H. (1975) Cont. Dermat. 1:136.
Ciccarelli, B.B., Hampton, T.H. and Jennette, K.W. (1981) Cancer Lett. 12:348.
Cooper, R.J., Langlois, D. and Olley, J. (1982) J. Appl. Toxicol. 2(2):99.
Cronin, E., DiMichiel, A.D. and Brown, S.S. (1980) in Nickel Toxicology Brown, S.S. and Sunderman, W.R., Eds., Academic Press, NY, 149.
Cruz, R.B., Lorouso, C., George, S., Thomassen, Y., Kinrade, J.D., Butler, L.R.P., Lye, J. and Van Loon, J.C. (1980) Spectrochim. Acta. 35B:775.
Cutter, G.A. (1985) Anal. Chem. 57:2951.
de Oliveira, E., McLaren, J.W. and Berman, S.S. (1983) Anal. Chem. 55:2047.
DeSilva, K.N. and Chatt, A. (1982) J. Trace Microprobe Tech. 1(3):307.
Eisenberg, M. and Topping, J.J. (1984) J. Environ. Sci. Health Part B. 19(7):649.
EPA (U.S. Environmental Protection Agency) (1979) Methods for Chemical Analy sis of Water and Waste, EPA-600/47902, Cincinnati, OH 45268.
EPA (U.S. Environmental Protection Agency) (1985) Drinking water criteria document for nickel. EPA Environmental Criteria and Assessment Office, EPA/600/X-84-193-1 Cincinnat i, OH.
EPA (U.S. Environmental Protection Agency) (1989) Ershow, A.G. and Cantor, K.P. Total water and tapwater intake in the United States: Population-based estimates of quantities and sources. National Cancer Institute Order #263-MD- 810264, EPA/600/8-89/043 Life Sciences Research Office, FASEB, Bethesda, MD, 3-8.
EPA (U.S. Environmental Protection Agency) (1991) Draft Fish Sampling and Analysis: A Guidance Document for Issuing Fish Advisories, Washington, DC 20460.
Favretto, L.G., Marletta, G.P. and Favretto, L. (1981) Developments in Food Analysis: Proceedings of the First European Conference on Food Chemistry in Euro Food Chem I, Vienna, Austria, 372.
Fernando, L.A., Heavner, W.D. and Gabrielli, C.C. (1986) Anal. Chem. 58:511.
FDA (U.S. Food and Drug Administration) (1975) National Shellfish Sanitation Program - Chemical Procedures, DHEW Publication No. (FDA) 76-2006, Washington, DC 20204.
FDA (U.S. Food and Drug Administration) (1989) Docket No. 89N-0014, RIN 095-Ac91, 11-30-89.
FDA (U.S. Food and Drug Administration) (1990) Inspection Operations Manual, Rockville, MD.
Gault, N.F.S., Tolland, E.L.C. and Parker, J.G. (1983) Mar. Biol. 77(3):307.
Gawkrodger, D.J. Cook, S.W., Fell, G.S., et al (1986) Br. J. Dermatol. 115:33.
Grant, W.A. and Ellis, P.C. (1988) J. Anal. At. Spectrom. 3:815.
Guy, R.D. (1985) Anal. Chim. Acta. 174:269.
Hall, R.A., Zook, E.G. and Meaburn, G.M. (March, 1978) National Marine Fisheries Service Survey of Trace Elements In Fishery Resource, Washington, DC.
Harms, U. (1985) Fresenius Z. Anal. Chem. 322:53.
Helrich, K., Ed. (1990) Official Methods of Analysis of the Association of Official Analytical Chemists, 15th Ed., Vol. I, Chap. 9, Method 972.23, AOAC, Arlington, VA.
Holak, W. (1969) Anal. Chem. 41:1712.
Horie, A., Haratake, J., Tanaka, I., Kodama, Y. and Tsuschya, K. (1985) Biol. Trace Elem. Res. 7:223.
Hu, I.- W. (1985) Analysis of Seafood Consumption in the U.S.: 1970, 1974, 1978, 1986. NTIS PB86-135043.
IARC (International Agency for Research on Cancer) (1976) In: IARC Monograph on the Evaluation of Carcinogenic Risk of Chemicals to Man, Vol. 11 Lyon, France, 75-112.
Ikeda, M., Nishibe, J., Hamada, S. and Tujino, R. (1982) Anal. Chim. Acta. 125:109.
Jones, J.W. (1988) Food Samples. In Quantitative Trace Analysis of Biological Materials, H. A. McKenzie and L. E. Smythe, Eds., Elsevier Science, New York, NY, 353.
Jordan, W.P. and King, S.E. (1979) J. Am. Acad. Dermatol. 1:508.
Julshamn, K., Ringdal, O., Slinning, K.E. and Braekkan, O.R. (1982) Spectroc him. Acta 37B(6):473.
Kaaber, K., Veien, N.K. and Tjell, J.C. (1978) Br. J. Determatol. 98:197.
Kaaber, K., Menne, T., Tjell, J.C. and Veien, N.K. (1979) Contact Dermatitis 5:221.
Kingston, H.M. and Jassie, L.B. (1986) Anal. Chem. 58:2534.
Kingston, H.M. and Jassie, L.B. (1988) Introduction to Microwave Sample Preparation, ACS, Washington, DC.
LaTouche, Y.D., Bennett, C.W. and Mix, M.C. (1981) Bull. Environ. Contam. Toxicol. 26:224.
Lemly, A.D. (1982) Environ. Technol. Lett. 3:497.
Lytle, T.F. and Lytle, J.S. (1982) Bull. Environ. Contam. Toxicol. 29:50.
Madrid, Y., Bonilla, M. and Camara, C. (1988) J. Anal. At. Spectrom. 3:1097.
Maher, W.A. (1981) Anal. Chim. Acta. 126:157.
Maher, W. (1982) Anal. Chim. Acta. 138:365.
Maher, W.A. (1983) Talanta 30:534.
Maher, W. (1986) Anal. Lett. 19:295.
Marcus, J. M. and Thompson, A.M. (1986) Bull. Environ. Contam. Toxicol. 36:587.
May, T.W. and McKinney, G. L. (1981) Pestic. Monit. J. 15(1):14.
May, T.W. (1982) J. Assoc. Off. Anal. Chem. 65:1140.
May, T.W. and Brumbaugh, W.G. (1982) Anal. Chem. 54:1032.
McCarthy, H. and Ellis, P.C. (1991) J. Assoc. Off. Anal. Chem. 74:566.
Mckie, J.C. (1985) Anal. Chim. Acta. 197:303.
McMahon, B.M. and Hardin, B.F. Eds. (1968) Pesticide Analytical Manual, Vol. I, 2nd Ed. and updates, U.S. Food and Drug
Administration, Rockville, MD.
McMahon, J.W., Docherty, A.E., Judd J.M.A. and Gentner, S-R. (1985) Int. J. Environ. Anal. Chem. 24:297.
Meeus-Verdinne, K. MPNBA, Van Cauter, R. and De Borger, R. (1983) Mar. Pollut. Bull. 14(5):198.
Micallef, S. and Tyler, P.A. (1989) Bull. Environ. Contam. Toxicol. 42(3):344.
Michie, N.D., Dixon, E.J. and Bunton, N.G. (1978) J. Assoc. Off. Anal. Chem., 61:48.
Miyaki, M., Akamatsu, N., Ono, T. and Koyama, H. (1979) Mutat. Res. 68:259.
Moody, J.R. and Lindstrom, R.M. (1977). Anal. Chem. 49:2264.
Montaser, A. and Golightly, D.W., Eds. (1987) Inductively Coupled Plasmas in Analytical Atomic Spectrometry VCH, New York, NY, 487-511.
MRCA (Market Research Corporation of America) (1988) 14 Day Survey (5-Year Census, 1982-87) Northbrook IL.
Munro, S., Ebdon, L. and McWeeny, D.J. (1986) J. Anal. At. Spectrom. 1:211.
Nadkarni, R.A. (1984) Anal. Chem. 56:2233.
NAS (National Academy of Sciences) (1975) Medical and biological effects of environmental pollutants: Nickel. NAS, Washington, D.C.
Newman, S.M., Summit, R.L. and Nunez, L.J. (1982) Mutat. Res. 101:67.
NOAA (National Oceanic and Atmospheric Administration) (1989) A summary of data on tissue contamination from the first three years (1986-1988) of the mussel watch project. Technical Memorandum NOS OMA 49, NOOA, Rockville, MD.
Norseth, T. Nickel. (1986) In Handbook on the Toxicology of Metals Friberg, L., Nordberg, G.F., and Vouk, V.B. Eds.
Elsevier, NY.
Ottolenghi, A.D., Haseman, J.K., Payne, W.W., Falk, H.L. and MacFarland, H.N. (1975) J. Natl. Cancer Inst. 54:1165.
Panaro, K.W. and Krull, I.S. (1984) Anal. Lett. 17:157.
Pao, E.M., Fleming, K.H., Guenther, P.M., et al. (1982), Foods commonly eaten by individuals: amount per day and per eating occasion. U.S. Department of Agriculture. Home Economics Report No. 44.
Park, C.J., Van Loon, J.C, Arrowsmith, P. and French, J.B. (1987) Anal. Chem. 59:2191.
Pennington, J.A.T., and Jones, J.W. (1987) J. Am. Diet. Assoc. 87:1644.
Poldoski, J.E. (1980) Anal. Chem. 53:1147.
Private Communication 1 Hans Kurner, Post FACH 171, D-8200 Rosenheim, Federal Republic of Germany.
Private Communication 2, Commonwealth of Virginia, Department of General Services, Division of Consolidated Laboratory Services.
Private Communication 3, P. C. Ellis, Rhode Island Dept. of Health, Division of Laboratories, 50 Orms St., Providence, RI 02904.
Private Communication 4, J. Anderson, Bureau of Chemistry, Division of Consolidated Laboratories, Commonwealth of Virginia, 1 North 14th St., Richmond, VA 23219.
Private Communication 5, K. Wiles, Texas Department of Health, Shellfish Sanitation Branch, 1100 W. 49th Street, Austin, Texas 78756.
Private Communication 6, E. Feerst, State of New Jersey, Department of Environmental Protection, Marine Water Classification and Analysis, P.O. Box 405, Stoney Hill Road, Leeds Point, NJ 08220.
Private Communication 7, G. Becking, WHO, International Program on Chemical Safety to I. Boyer, FDA, 6/26/90.
Robbins, W.B. and Caruso, J.A. (1979) Anal Chem. 51:889A.
Robison, S.H. and Costa, M. (1982) Cancer Lett. 15:35.
Saxholm, H.J.K., Reith, A. and Brogger, A. (1981) Cancer Res. 41:4136.
Schnitzer, G., Pellerin, C. and Clouet, C. (1988) Lab. Pract. 37(1):63.
Serra, T.M. and Serrano, J.F.B. (1984) J. Assoc. Off. Anal. Chem. 67(1):186.
Stephenson, M.D., Martin, M., Lange, S.E., Flegal, A.R. and Martin, J.H. (1979) California mussel watch 1977-78. Volume II: Trace metals concentrations in the California mussel, Mytilus californianus, State Water Resources Control Board, Water Quality Monitoring Report, No. 79-22, Sacramento, CA.
Stephenson, M.D. and Smith, D.R. (1988) Anal. Chem. 60:696.
Sturgeon, R.E., Willie, S.N. and Berman, S.S. (1986) J. Anal. At. Spectrom. 1:115.
Sunderman, F.W. Jr. (1977) Ann. Clin. Lab. Sci. 7:377.
Sunderman, F.W. Jr. (1984) Toxicol Environ. Chem. 8:235.
Sunderman, F.W. Jr. (1988) In Handbook of Toxicity of Inorganic Compounds, Seiler,H.G. and Sigel, H., Eds., Dekker, New York, NY. 453-468.
TRF (Tuna Research Foundation) (1975), Seafood Consumption Study, National Purchase Diary Panel, Inc., Scahumsburg IL.
Veien, N.K., Hattel, T., Justesen, O, et al. (1982) Cont. Derma. 8:373.
Watling, H.R. and Watling, R.J. (1982) Bull. Environ. Contam. Toxicol. 28:460.
Welz, B. and Melcher, M. (1985) Anal. Chem. 57:427.
Welz, B. and Schlemmer, G. (1986) J. Anal. At. Spectrom. 1:119.
Whanger, P.D. (1973) Toxicol. Appl. Pharmacol. 25:323.
White, R.T. Jr. and Douthit, G.E. (1985) J. Assoc. Off. Anal. Chem. 68:766.
Willie, S.N., Sturgeon, R.E. and Berman, S.S. (1986) Anal. Chem. 58:1140.
WHO (World Health Organizatiob) (1983) "Guidlines for the Study of Dietary Intakes of Chemical Contaminants." In Global Environmental Monitoring System WHO, Geneva, Switzerland, 49-50.
Zeisler, R., Stone, S.F. and Sanders, R.W. (1988) Anal. Chem. 60:2760.
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.