Safety evaluation of dietary aluminum.

Aluminum is a nonessential metal to which humans are frequently exposed. Aluminum in the food supply comes from natural sources, water used in food preparation, food ingredients, and utensils used during food preparations. The amount of aluminum in the diet is small, compared with the amount of aluminum in antacids and some buffered analgesics. The healthy human body has effective barriers (skin, lungs, gastrointestinal tract) to reduce the systemic absorption of aluminum ingested from water, foods, drugs, and air. The small amount of aluminum (<1%) that is systemically absorbed is excreted principally in the urine and, to a lesser extent, in the feces. No reports of dietary aluminum toxicity to healthy individuals exist in the literature. Aluminum can be neurotoxic, when injected directly into the brains of animals and when accidentally introduced into human brains (by dialysis or shrapnel). A study from Canada reports cognitive and other neurological deficits among groups of workers occupationally exposed to dust containing high levels of aluminum. While the precise pathogenic role of aluminum in Alzheimer's disease (AD) remains to be defined, present data do not support a causative role for aluminum in AD. High intake of aluminum from antacid for gastrointestinal ailments has not been reported to cause any adverse effects and has not been correlated with neurotoxicity or AD. Foods and food ingredients are generally the major dietary sources of aluminum in the United States. Cooking in aluminum utensils often results in statistically significant, but relatively small, increases in aluminum content of food. Common aluminum-containing food ingredients are used mainly as preservatives, coloring agents, leavening agents, anticaking agents, etc. Safety evaluation and approval of these ingredients by the Food and Drug Administration indicate that these aluminum-containing compounds are safe for use in foods.

Toxicity and mutagenicity studies of DN-50000((R)) and RP-1((R)) enzymes.

Improved yields of 5'-nucleotides from yeast extract for food flavouring purposes is possible through use of microbial nucleotidases, which will be available to food processors as the flavour enhancer Aromild. The safety of these enzymes, 5'-phosphodiesterase (RP-1) and the 5'-adenylic deaminase (DN-50000) was investigated in male and female rats. Feeding rats a diet admixed with 500, 2000 and 8000 mg/kg body weight of DN-50000 for 35 days resulted in no significant dose-related changes in body weight, water consumption, urinalysis, haematological profiles, blood chemistry or histopathological profiles of either male or female rats from consumption of the enzyme preparation. There was an increase in the absolute and/or relative organ weights of the submaxillary (salivary) glands in both sexes at 8000 mg/kg. The no-observed-effect level (NOEL) for DN-50000 was clearly evident at 2000 mg/kg. Consumption of RP-1 enzyme for 35 days at dietary levels of 500, 2000 and 8000 mg/kg body weight resulted in no significant changes in the above mentioned parameters, which could be directly attributed to a dose-related effect, with the exception of an increase in the absolute and relative weights of submaxillary glands of both male and female rats in the 2000 and 8000 mg/kg groups. The increase in weight of the submaxillary glands was associated with histological evidence of acinar cell hypertrophy. The NOEL for dietary consumption of RP-1 was clearly evident at 500 mg/kg. In a follow-up study in which rats were gavaged with 2000 mg/kg RP-1, submaxillary gland hypertrophy did not occur. These studies suggest that DN-50000 and RP-1 exert an action on submaxillary glands similar to that which has been previously reported for the enzyme pancreatin. Neither DN-50000 nor RP-1 were mutagenic in the Ames assay using Salmonella typhimurium strains TA100, TA1535, TA98, TA1537 or Escherichia coli strain WP2uvrA, in the presence or absence of S9 mix.

A review of the studies of the safety of polydextrose in food.

Polydextrose (CAS no. 68424-04-4) is a water-soluble polymer of glucose that provides to foods the bulk and texture of sucrose. There are two main forms of polydextrose, an acidic form (PD-A) and a neutralized potassium salt (PD-N). Polydextrose is resistant to mammalian metabolic and microbial degeneration, rendering it both low in caloric value and non-cariogenic. Little polydextrose is absorbed intact although some is metabolized by caecal/colonic bacteria. At high enough levels of ingestion, this bacterial metabolism results in flatus, bloating, loose stools and ultimately a frank diarrhoea. Microbial metabolism also produces some volatile fatty acids that are absorbed by the animal and have calorigenic value. The species and dose threshold for persistent loose stools/watery diarrhoea determines the degree of electrolyte loss by the animal. In the dog, an obligate carnivore, sodium-sparing activity by the kidney and concomitant and obligatory calcium reuptake result in a well-defined aetiology of hypercalcaemia and subsequent nephrocalcinosis, particularly for PD-N. Of the species tested, the dog was the most sensitive to this carbohydrate with a no-effect level of 2000 mg/kg body weight/day. Omnivores, including the rat, mouse and monkey, have a no-effect level ranging from 2500 to 10,000 mg/kg body weight/day. No toxicity has been demonstrated in man, although the dose for laxation (to be distinguished from diarrhoea) is approximately 90 g/day (v. sorbitol at 70 g/day). Polydextrose did not show any reproductive toxicity, teratology, carcinogenesis, mutagenicity or genotoxicity. Polydextrose has been approved for food additive use (21 CFR 172.841) in the US, and an "ADI not specified" by the Joint WHO/FAO Expert Committee on Food Additives (JECFA, 1987). It has been approved in over 50 countries around the world and has been used extensively in the diet for over15 years. Specification monographs are published in the Food Chemicals Codex (FCC) (NAS, 1996) and the FAO Compendium (JECFA, 1995). This review provides an overview of the studies and salient data, not previously reported in the scientific literature, which had been submitted to regulatory agencies in support of these approvals.

Evaluation of safety of inulin and oligofructose as dietary fiber.

In the United States, most individuals consume far less dietary fiber than the daily value (DV) set at 25 g. The average daily consumption for inulin and oligofructose is estimated to be between 1 and 4 g in this country, with a higher intake of 3 to 11 g seen in Europe. Inulin and oligofructose are soluble, fermentable dietary fibers, of low net caloric value having many of the possible health benefits attributed to fiber. Such fiber consists of poly- and oligomers of fructose joined by beta(2-->1) fructosyl-fructose bonds. This class of fiber has been studied in a series of standard toxicological test systems. The studies have demonstrated that inulin-type fructans, when administered in the diet at high levels, do not result in mortality, morbidity, target organ toxicity, reproductive or developmental toxicity, or carcinogenicity. Several in vitro studies have also shown the absence of mutagenic or genotoxic potential. The only basis for limiting use of such fiber in the human diet relates to gastrointestinal tolerance. A series of clinical studies has been reported which shows that up to 20 g/day of inulin and/or oligofructose is well tolerated. As foods marketed in the United States bear labels stating both the quantity per serving size and the corresponding percentage of the daily value (% DV) of fiber, consumers can make appropriate choices and decisions about daily consumption without exceeding individual tolerance.

Does the term carcinogen send the wrong message?

The term carcinogen has been used by scientists and health regulatory officials for decades. During the last 20 years there have been attempts to redefine the term to make it more rigorous. But, as predicted two decades ago by a benchmark-setting subcommittee of the National Cancer Advisory Board, advances in scientific understanding have brought about dramatic changes in the way we are able to view the term carcinogen. These changes, their scientific bases and their effect on defining the term carcinogen are described. An alternative to the use of the term carcinogen is suggested by the recently proposed US Environmental Agency's guidelines for cancer risk assessment which appear to be in accord with current scientific understanding and the importance of considering the factors affecting the term carcinogen. The guidelines set forth four questions, the answers to which could, in our judgment, replace the need to define or use the term carcinogen which, in light of new scientific knowledge, has become more misleading than useful.

Multiple chemical sensitivities: a symposium on the state of the science.

Multiple chemical sensitivities (MCS) defies diagnostic categorization because of its pansystemic manifestations, its lack of consistent symptomatology, and its absence of specific, measurable endpoints, either physical stigmata or laboratory findings. Controlled studies have been few and difficult to perform. Moreover, the phenomenon resists systematic investigation for two reasons. First, it has coalesced into a movement championed by zealous proponents and organized adherents. Second, it has gained support in the courts, the legislatures, and the regulatory agencies which have provided special protection and monetary awards to this phenomenon before science and medicine have defined it as a medical disorder. One hotly contested issue in the MCS debate is the relative role of organic versus psychological contribution to the symptoms of MCS patients. This is a critical issue most importantly because it determines approaches to treatment, secondarily because it affects regulatory action, disability determination, and compensability. The interest of the ISRTP in this phenomenon derives from the significant regulatory impact of this diagnosis on OSHA standards, EPA regulations, and FDA standards. The symposium was convened to explore the quality of the science underlying MCS with respect to diagnosis, and, particularly, to cause. The general objective of the symposium was to discuss the state of the science regarding MCS and its implications in regulatory toxicology and public health. The panel of speakers represented a variety of disciplines including toxicology, immunology, occupational medicine, psychiatry, psychology, epidemiology, and public health. The symposium was attended by a diverse audience representing the medical, scientific, business, legal, and regulatory communities. The majority of speakers critically questioned the characterization of MCS as a clinical entity, in light of historical comparisons to earlier false diagnoses, toxicological implausibility, and clinical inconsistencies.

How sick a patient? Report of a workshop on cancer risk assessment.

A report by the U.S. Government Office of Management and Budget (OMB) criticized the way health, safety, and environmental regulation of potential cancer causing substances is conducted by federal agencies, especially the Environmental Protection Agency. Cancer risk assessment--this report indicates--is governed by arbitrary policy assumptions and procedures improperly disguised as scientific and is designed to overestimate risk. Unwarranted economic burdens of ensuing regulation may then adversely affect standards of living and ultimately the very health and longevity that regulation is presumed to safeguard. An interdisciplinary workshop generally agreed with the OMB position and sharpened criticism of the procedures and scientific pretensions in the regulation of potential carcinogens. Various options for change were discussed, although it was felt that the success of detailed remedies would require a wider political, administrative, and scientific discourse.

The human relevance of the renal tumor-inducing potential of d-limonene in male rats: implications for risk assessment.

The monoterpene d-limonene is a naturally occurring chemical which is the major component in oil of orange. Currently, d-limonene is widely used as a flavor and fragrance and is listed to be generally recognized as safe (GRAS) in food by the Food and Drug Administration (21 CFR 182.60 in the Code of Federal Regulations). Recently, however, d-limonene has been shown to cause a male rat-specific kidney toxicity referred to as hyaline droplet nephropathy. Furthermore, chronic exposure to d-limonene causes a significant incidence of renal tubular tumors exclusively in male rats. Although d-limonene is not carcinogenic in female rats or male and female mice given much higher dosages, the male rat-specific nephrocarcinogenicity of d-limonene may raise some concern regarding the safety of d-limonene for human consumption. A considerable body of scientific data has indicated that the renal toxicity of d-limonene results from the accumulation of a protein, alpha 2u-globulin, in male rat kidney proximal tuble lysosomes. This protein is synthesized exclusively by adult male rats. Other species, including humans, synthesize proteins that share significant homology with alpha 2u-globulin. However, none of these proteins, including the mouse equivalent of alpha 2u-globulin, can produce this toxicity, indicating a unique specificity for alpha 2u-globulin. With chronic exposure to d-limonene, the hyaline droplet nephropathy progresses and the kidney shows tubular cell necrosis, granular cast formation at the corticomedullary junction, and compensatory cell proliferation. Both d-limonene and cis-d-limonene-1,2-oxide (the major metabolite involved in this toxicity) are negative in in vitro mutagenicity screens. Therefore, the toxicity-related renal cell proliferation is believed to be integrally involved in the carcinogenicity of d-limonene as persistent elevations in renal cell proliferation may increase fixation of spontaneously altered DNA or serve to promote spontaneously initiated cells. The scientific data base demonstrates that the tumorigenic activity of d-limonene in male rats is not relevant to humans. The three major lines of evidence supporting the human safety of d-limonene are (1) the male rat specificity of the nephrotoxicity and carcinogenicity; (2) the pivotal role that alpha 2u-globulin plays in the toxicity, as evidenced by the complete lack of toxicity in other species despite the presence of structurally similar proteins; and (3) the lack of genotoxicity of both d-limonene and d-limonene-1,2-oxide, supporting the concept of a nongenotoxic mechanism, namely, sustained renal cell proliferation.(ABSTRACT TRUNCATED AT 400 WORDS)

Critical assessment of carcinogenic risk policy.

Fact. Cancer is a relatively common yet greatly feared disease. Belief. The concept that cancer is largely preventable is widely held by advocate groups, the press, and Congress. Belief. The concept that carcinogens at any level of exposure pose a significant cancer risk to human is widely believed by the public. Fact. In contrast to this belief, carcinogens are now known to be widespread in the environment and that virtually all substances are contaminated with carcinogens at some albiet low level. Fact. The solution to the ubiguitous presence of carcinogens cannot be solved by regulatory fiat. Fact. Often the only viable solution to regulating carcinogens is setting maximum levels of acceptable exposure (tolerances). Belief. In U.S. society, the process of establishing tolerances must be conducted in the open, providing adequate opportunity for public comment. Fact. The courts will sustain regulatory agency decisions about risks only if the administrative procedures used comply with the Administrative Procedures Act and if the technical methodology used is in good standing. Fact. For the method to be in good standing it cannot be a recent invention created after the fact to solve the issue at hand but must instead be a procedure that is claimed to be generally applicable to determining or estimating cancer risk. Belief. QRA should be an orderly procedure or process by which cancer risk estimations are conducted in an unbiased manner. As such it is fundamentally acceptable to the courts for resolving disputes. Fact. However, because QRA is dependent upon a large number of assumptions and because regulatory agencies feel compelled to act in a conservative, risk-adverse manner, risk estimates are often criticized for being over stated. Belief. To make risk estimates more realistic, data or facts must substitute for worst case assumptions. Fact. This process of substituting scientific facts for assumptions is occurring but it is expensive, time consuming, and not always possible. Nevertheless, it constitutes a major opportunity for improving the process by which risk estimates are made.

FDA procedures and policies to estimate risks of injury to the male reproductive system.

Two decades ago, the Food and Drug Administration (FDA) undertook a testing and research program to study and assess the mutagenic properties of so-called "Generally Recognized as Safe" (GRAS) substances which have a long history of use in food. Initially, the program employed three highly regarded mutagenicity tests; the host mediated assay, somatic cell cytogenetics, and the dominant lethal test. Only the latter measures male germ cell events. Eventually, research and testing results revealed major problems in the deployment of these tests for such purposes. A new approach involving a three tiered system was instituted in which the first tier was a relatively inexpensive pre-screen ostensibly capable of detecting any and all potential mutagens. For reasons of economy, this pre-screen used micro-organisms. The objective of the second tier was to determine if substances positive in the first tier of tests would be mutagenic for higher organisms. Gene mutation in mammalian cells in culture, gene plus chromosomal mutation in Drosophila and heritable translocation in male mice were used for this purpose. The final tier was intended to assess the quantitative risk of mutation in mammals and depended entirely upon genetic studies in animals. Again, the heritable translocation test would be used as well as the specific locus test in mice. At the same time, efforts were made to refine and improve the usefulness of the dominant lethal and the heritable translocation test for toxicological purposes. More recently, studies have been undertaken to develop a practical test for nondisjunction in male germ cells. Currently, standard test requirements for food additive approval include only short-term in vitro mutagenicity tests.(ABSTRACT TRUNCATED AT 250 WORDS)

Beryllium: laboratory evidence.

Beryllium-containing compounds have been studied extensively and have been known to be carcinogenic in animals since 1946. Beryllium salts and alloys were among the first nonradioactive, inorganic substances shown to induce osteogenic sarcoma in experimental animals. Beryllium-containing compounds have been demonstrated to be powerful pulmonary carcinogens in rats. To date, these compounds do not appear to be mutagenic, leaving open the question of their mechanism of action.

Nitrates: laboratory evidence.

Neither nitrate nor nitrite per se has been demonstrated to produce cancer in experimental animals. The potential carcinogenicity of either of these substances would appear to derive from their involvement in the production of carcinogenic N-nitroso compounds. The extent to which such compounds form has been the subject of numerous studies.