3. The toxicological evaluation of compounds on the agenda: 3.4 Inorganic tin.(EVALUATION OF CERTAIN FOOD CONTAMINANTS)

3.4 Inorganic tin

Explanation

Inorganic tin is found in food in the +2 and +4 oxidation states; it may occur in cationic form (stannous and stannic compounds) or as anions (stannites or stannates). Inorganic tin was evaluated by the Committee at its fourteenth, fifteenth, twenty-second, twenty-sixth, thirty-third and fifty-fifth meetings (Annex 1, references 22, 26, 47, 59, 83 and 149). At its thirty-third meeting, the Committee converted the previously established provisional maximum tolerable daily intake (PMTDI) of 2 mg/kg of body weight to a provisional tolerable weekly intake (PTWI) of 14 mg/kg of body weight. At these meetings, the Committee reviewed data from short- and long-term dietary studies and noted that inorganic tin compounds generally have low systemic toxicity in animals because of limited absorption from the gastrointestinal tract, low accumulation in tissues, and rapid passage through the gastrointestinal tract. Insoluble tin compounds are less toxic than soluble tin salts.

At its Thirty-first Session, CCFAC asked the Committee to review information on the toxicity of inorganic tin in order to establish an ARfD (23). At its fifty-fifth meeting (Annex 1, reference 149), the Committee considered studies of the acute toxic effects seen after consumption of foods containing high concentrations of inorganic compounds of tin. It concluded that the acute toxicity of inorganic tin in animals and humans, however, results from irritation of the mucosa of the gastrointestinal tract, which may lead to vomiting, diarrhoea, anorexia, depression, ataxia, and muscular weakness. There was no clear dose-response relationship, and the vehicle in which the tin was administered may have affected its toxicity. The Committee concluded that insufficient data were available to establish an ARfD for inorganic tin. At that meeting, the PTWI previously established for compounds containing inorganic tin was not reconsidered and was retained at its current value. The Committee did not consider studies on organic tin compounds, since it had concluded at its twenty-second meeting (Annex 1, reference 47) that these compounds, which differ considerably from inorganic tin compounds with respect to toxicity, should be considered separately.

At its Thirty-fifth session, CCFAC (22) decided to ask the Committee to evaluate current levels of inorganic tin in "canned food other than beverages" and "canned beverages", and to determine an ARfD, since new data would become available. At its Thirty-sixth session (8), CCFAC asked the Committee, when possible, to take population sensitivity into consideration when considering the new data and to assess the likelihood of the occurrence of effects at the proposed draft MLs (200 mg/kg in canned beverages and 250 mg/kg in canned foods other than beverages).

At its present meeting, the Committee reconsidered studies of the acute toxic effects seen in humans after consumption of foods containing high concentrations of inorganic compounds of tin, and also considered a new study.

Observations in humans

Episodes of human poisoning resulting from consumption of food and drink contaminated with inorganic tin have resulted in abdominal distension and pain, vomiting, diarrhoea, and headache. Symptoms commonly start within 0.5-3h and recovery occurs within 48h. The doses of inorganic tin ingested in such episodes of poisoning were not estimated, but the symptoms occurred when canned food or beverages were found to contain tin at concentrations varying from 250 to 2000 mg/kg.

In one study, all five volunteers experienced symptoms when they ingested orange juice containing inorganic tin at a concentration of 1370 mg/kg (equal to a dose of 4.4-6.7 mg/kg of body weight). Orange juice containing inorganic tin at concentrations of 498, 540 or 730 mg/ kg (equal to a dose range of 1.6-3.6 mg/kg of body weight) did not provoke any symptoms in groups of five volunteers. Administration of the same amount of the same juice (containing tin at 1370 mg/kg) to these individuals 1 month later resulted in symptoms in only one person. Although this was explained by the authors as development of tolerance, another possible explanation might be that the longer storage of the juice led to a different speciation.

A newly available study (24) showed that tomato juice freshly spiked with tin (II) chloride at a concentration of [greater than or equal to] 161 mg/kg causes gastrointestinal disorders in humans in a concentration-related manner. The concentration-response relationship indicated a threshold for acute effects caused by inorganic tin at a concentration of about 150 mg/kg of juice. In the second part of this study, volunteers receiving 250 ml of a tomato soup contaminated with inorganic tin that had migrated from packaging at concentrations of <0.5,201 and 267 mg/kg did not experience an increased incidence of adverse effects compared with controls. The results of distribution studies of tin in the soup and juice consumed supported the view that both complexation and adsorption of tin onto solid matter reduce its irritant effect on the gastrointestinal tract.

Overall, the information available showed that gastrointestinal irritation from inorganic tin in canned foods is more closely related to the concentration and nature of tin in the product than to the dose of tin ingested on a body-weight basis. No information was available regarding subpopulations such as children or people with gastrointestinal disorders.

Prevention and control

The lacquering of tinplated cans prevents the migration of inorganic tin into food and beverages. Food and beverages should not be stored in opened tinplated cans.

Levels and pattern of food contamination

Data on the concentrations of inorganic tin in a range of foods from four countries (Australia, France, Lithuania and the UK) had become available since the last review of inorganic tin by the Committee and were reviewed at this meeting. The Committee noted that the reported concentrations of inorganic tin were in the same range as those previously assessed by the Committee, the new values ranging from "not detected" to 300 mg/kg.

Food consumption and dietary intake assessment

The major dietary source of inorganic tin is food packaged in unlacquered or partially lacquered tinplated cans. The migration of inorganic tin from tinplate into foods is greater in highly acidic foods such as pineapples and tomatoes: with increased time and temperature of food storage; and in foods, such as fruit juice, in opened cans. The inorganic tin content of canned foods is variable, and some foods may have concentrations high enough to cause an acute toxic reaction. Information previously evaluated by the Committee and additional data from Australia and the UK indicated that the mean long-term dietary intakes of inorganic tin by individuals ranged from <1 to about 14 mg/person per day. Population groups with higher intakes of canned foods may have higher intakes of inorganic tin. A small number of estimates of short-term dietary intake (i.e. in a period of 24 h or less) were assessed by the Committee. Based on limited data, preliminary short-term intakes of inorganic tin were estimated to be between 0.004 and 3.3 mg/kg of body weight per day, depending on the food considered.

Evaluation

The Committee concluded that the data available indicated that it is inappropriate to establish an ARfD for inorganic tin, since whether or not irritation of the gastrointestinal tract occurs after ingestion of a food containing tin depends on the concentration and nature of tin in the product, rather than on the dose ingested on a body-weight basis. Therefore, the Committee concluded that the short-term intake estimates were not particularly relevant for the assessment, as they were estimated likely doses of total inorganic tin. The Committee reiterated its opinion, expressed at its thirty-third and fifty fifth meetings, that the available data for humans indicated that inorganic tin at concentrations of >150 mg/kg in canned beverages or 250 mg/kg in canned foods may produce acute manifestations of gastric irritation in certain individuals. Therefore ingestion of reasonably-sized portions of food containing inorganic tin at concentrations equal to the proposed standard for canned beverages (200 mg/kg) may lead to adverse reactions. No information was available as to whether there are subpopulations that are particularly sensitive for such adverse reactions. The Committee reiterated its advice that consumers should not store food and beverages in opened tinplated cans.

In addition, the Committee noted that the basis for the PMTDI and PTWI established at its twenty-sixth and thirty-third meetings was unclear and these values may have been derived from intakes associated with acute effects. The Committee concluded that it was desirable to (re)assess the toxicokinetics and effects of inorganic tin after long-term exposure to dietary doses of inorganic tin at concentrations that did not elicit acute effects.

An addendum to the toxicological monograph was prepared.

3.5 Polybrominated diphenyl ethers

Explanation

Polybrominated diphenyl ethers (PBDEs) are anthropogenic chemicals that are added to a wide variety of consumer/commercial products (e.g. plastics, polyurethane foam, textiles) in order to improve their fire resistance. PBDEs have been produced primarily as three main commercial products: pentabromodiphenyl oxide or ether (pentaBDE), octabromodiphenyl oxide or ether (octaBDE) and decabromodiphenyl oxide or ether (decaBDE). Some variability in composition is known to exist between products from different manufacturers, but each technical product can be approximately described by their congener compositions, given in Table 9. Theoretically, as with polychlorinated biphenyls (PCBs), 209 distinct PBDE isomers are possible; however, each commercial mixture usually only contains a limited number of congeners from each homologue group. The worldwide demand for PBDEs in 2001 was estimated to be almost 70000 tonnes, with decaBDE accounting for almost 80% of the total market.

PBDEs have not been evaluated previously by the Committee. In 1994, WHO published an Environmental Health Criteria document on brominated diphenyl ethers (25), as part of an overview on the possible environmental and human health impacts of flame retardants. Recent analysis of archived samples collected over the last three to four decades has demonstrated significant increases in concentrations of PBDEs in samples from the environment and in certain samples from humans in Europe and North America. This has led to both voluntary and formal bans on the production and use of certain formulations of PBDEs. Limited national food surveys have identified diet as one of the possible main sources of human exposure. The present evaluation was undertaken in response to a request from CCFAC, most recently at its Thirty-fifth Session (22), to evaluate the potential risks associated with the presence of PBDEs in food.

Absorption, distribution, metabolism and excretion

The majority of detailed studies of the absorption, distribution, metabolism and excretion of PBDEs are limited to the individual congeners BDE-47, -99 and -209. The absorption of PBDEs is directly related to the extent of bromination of the parent diphenyl ether; as a general rule, greater substitution with bromine leads to a decrease in bioavailability. Intestinal absorption of decaBDE is limited, with >90% of an orally administered dose being rapidly excreted in the faeces. For congeners with a lower degree of bromination (tetra and penta-substituted), >80% of an orally administered dose is absorbed, with patterns of distribution in tissue being largely determined by lipid content. The metabolism of PBDEs consists of hydroxylation and methoxylation reactions and, in the case of congeners with a higher degree of bromination, oxidative debromination. Faecal excretion appears to be the predominant route of elimination; however, some differences exist between species. Urinary excretion of BDE-47 is a minor pathway in rats, but in mice is as important as faecal excretion. Limited data were available regarding the half-lives of individual PBDE congeners; however, preliminary values in female rats exposed to a commercial pentaBDE mixture, Bromkal 70-5 DE, ranged from 30 to 90 days for the tetra- to hexa-substituted congeners.

Limited pharmacokinetic data were available for humans. On the basis of the observed increase in concentrations of PBDEs in tissue with time, PBDEs are absorbed and bioaccumulate.

Toxicological data

In the toxicological studies reviewed, PBDEs were administered by the oral (gavage or diet) route of exposure, unless otherwise stated.

The acute toxicity of mixtures of PBDEs is low in rodents. Generally, even at the highest doses (several grams/kg of body weight), there are no observable effects in standard tests for acute toxicity after exposure to decaBDE and octaBDE, although certain effects (increased mortality, behavioural symptoms and changes in gross pathology) are seen after exposure to pentaBDE at similar high doses. Induction of enzymes, changes in levels of hormones and neurobehavioural effects are observed after bolus administration of mixtures of PBDEs (pentaBDE and octaBDE), and of specific congeners at considerably lower doses. In short-term studies of toxicity, the main effects of mixtures of PBDEs were seen in the liver, kidney and thyroid of both sexes. Enlargement of the liver is a common finding, which may be connected to increased activity of microsomal enzymes in the liver. Histological changes occur in liver (enlargement, "round bodies", vacuolization, necrosis), kidney (hyaline degenerative cytoplasmic changes) and thyroid (hyperplasia). In short-term studies, effects on thyroid hormone, vitamin A homeostasis and microsomal enzymes were observed at doses of 1-10 mg/kg of body weight per day.

The only long-term study with PBDEs was conducted with the decaBDE mixture. In this National Toxicology Program study of carcinogenicity (26), decaBDE (purity, 94-99%: brominated dioxins and furans reported not to be detected), given in the diet at high concentrations (2.5% or 5%) for 111-113 weeks, significantly increased the combined incidence of hepatocellular adenomas and carcinomas in male mice, but not in female mice. In spite of an increase in follicular cell hyperplasia, the incidence of thyroid follicular cell adenoma/carcinoma was not significantly increased. In male and female rats, the incidence of liver adenomas, but not hepatocellular carcinomas, was increased. Other effects, such as liver hypertrophy, granulomas, thrombosis and degeneration, thyroid follicular cell hypertrophy, and lymphoid hyperplasia, were also noted. The Committee concluded that evidence for the carcinogenicity of decaBDE in experimental animals was limited, and noted that no information was available on the carcinogenic potential of the other PBDE mixtures.

The results of the majority of tests for genotoxicity performed in vitro (point mutations, chromosomal aberrations, unscheduled DNA synthesis, sister chromatid exchange) and limited data from tests in vivo (chromosomal aberration) indicated that PBDE mixtures and individual congeners are not genotoxic.

The developmental toxicity of deca-, octa- and pentaBDE mixtures has been studied in rats and rabbits. In rats, preparations of pure decaBDE (purity, 97-98%) had no effects on developmental parameters, while decaBDE of lower purity (decaBDE, 77.4%; nonaBDE, 21.8%: octaBDE, 0.8%) caused fetotoxic effects. Exposure to commercial octaBDE mixtures (Saytex 111 and DE-79) produced developmental toxicity as indicated by increased numbers of late resorptions, reduced fetal weight, severe oedemas, reduced ossification of skull bones and bent rib and limb bones at a dose range of 10-50 mg/kg of body weight per day; only slight maternal toxicity (decreased body weight) was observed at doses of 25-5 mg/kg of body weight per day. A pentaBDE mixture (Saytex 115) has only been tested in one study, with no clear adverse effects at a dose of 100 mg/kg of body weight per day.

In rabbits given a commercial octaBDE mixture (Saytex 111) during gestation, no major fetotoxic effects were observed, but an increase in the incidence of delayed ossification of sternebrae was seen at 15 mg/ kg of body weight per day.

The Committee concluded that the embryo and fetus may be more sensitive to PBDEs than maternal animals, and that exposure to octaPBDE mixtures causes an increase in the incidence of developmental abnormalities.

Special studies

Studies with purified PBDE congeners in vitro have shown lack of activation of the aryl hydrocarbon receptor at doses six orders of magnitude higher than …