Dietary administration

Studies on rats had shown no toxicity of astaxanthin preparations. Dietary administration of astaxanthin has proved to significantly inhibit carcinogenesis in the mouse urinary bladder, rat oral cavity, and rat colon. In addition, it is reported to induce xenobiotic-metabolizing enzymes in rat liver. 

Tanaka, T. et al., Suppression of azoxymethane-induced rat colon carcinogenesis by dietary administration of naturally occurring xanthophylls astaxanthin and canthaxanthin during the post-initiation phase, Carcinogenesis, 16, 2957, 1995. 

Kresty, L.A. et al., Chemoprevention of esophageal tumorigenesis by dietary administration of lyophilized black raspberries. Cancer Res., 61, 6112, 2001. 

Intermediate-duration oral exposure to Durad 110 produced deaths in chickens associated with the delayed development of neuropathy at dosage levels of 4,000 mg/kg/day in a 28-day study and 90 mg/kg/day in a 90-day study (FMC 1986). At 100 mg/kg/day over a 13-week period, 2 of 12 male and 1 of 12 female rats died with exposure to tri- -butyl phosphate (Healy et al. 1995). Dietary administration of Pydraul 90E for 90 days providing daily doses of 50 mg/kg/day produced no chemical-related deaths in rats (Monsanto 1979). An organophosphate ester hydraulic fluid designated MIL-H-83306 also caused death in 4 of 4 rats exposed by gavage to 1,000 mg/kg over a 26-day period (Mattie et al. 1993). 

A 2-year carcinogenicity bioassay of tricresyl phosphate in mice and rats showed no evidence of carcinogenicity in these species (NTP 1994). Doses (consumed in feed) were <37 mg/kg/day in mice and < 15 mg/kg/day in rats. Dietary administration of tributyl phosphate was associated with transitional and squamous cell carcinomas of the bladder in rats after 2 years of exposure at 143.3 mg/kg/day (FMC 1994a). An increased incidence of hepatocellular adenomas in the liver was observed in mice after dietary administration of 455 mg/kg/day tributyl phosphate for 18 months (FMC 1994b). 

Lethal dietary administration of lead acetate, Before death, birds were emaciated and 13... 

Figure 14.1 Structures of chlorpyrifos and some of its metabolites. (Modified from Barron, M.G., S.M. Plakas, and PC. Wilga. 1991. Chlorpyrifos pharmacokinetics and metabolism following intravascular and dietary administration in channel catfish. Toxicol. Appl. Pharmacol. 108 474-482.)...

Food consumption (actually measured to ensure that dietary administration doses are accurate). 

In mallard ducks, dietary administration of endrin (0.5 or 3 ppm) had no effects on egg production, fertility, and ability to hatch, or 14-day hatchling survival, although a 9.6% drop in embryo survival was observed at the high dose (Roylance et al. 1985). 

Rivett KF, Bhatt A, Street AE, et al. 1972. Thio-demeton/oral toxicity to mice/dietary administration for three months. Huntington Research Centre, England. Report No. 5505/72/901. 

Dietary administration of heptachlor (97.6% purity) at 0.65 or 1.3 mg/kg/day for 25 weeks promoted the development of hepatocellular foci and hepatocellular neoplasms in male B6C3F i mice previously initiated with 3.8 mg/kg/day diethyinitrosamine in drinking water for 14 weeks (Williams and Numoto 1984). These results indicate that heptachlor acts as a liver tumor promoter in male mice. 

Hazleton Laboratories (1968) 13-Week Dietary Administration—Dogs Plasticiser (DIDP) submitted to WR Grace and Company... 

Ito et al. (1995) examined the combined dietary administration to rats of 19 organophosphate pesticides and 1 organochlorine pesticide, aU permitted for use in Japan, each at its ADI level. The dietary exposure at this level did not enhance the development of diethyl nitrosamine initiated pre-neoplastic lesions whereas at 100 times the ADI, the number and area of lesions were increased. The authors concluded that the study provided direct support for the present use of the safety factor approach in the quantitative hazard evaluation of pesticides. 

The carcinogenicity of ethylenimine has been investigated in animal studies. Rats given subcutaneous injections twice weekly for 33 weeks developed sarcomas at the injection site. Administered to mice by gavage for 3 weeks, followed by dietary administration for 77 weeks, it caused a significant increase in hepatomas and pulmonary tumors. ... 

No excess of cancer was reported in two follow-up smdies of affected individuals in Turkey about 20-30 years after consumption of contaminated grain had ceased. " In mice, liver tumors were observed after exposure to HCB at 12-24mg/kg/day in the diet, but not at 6mg/kg/day. Hepatomas, hepatocellular carcinomas, bile duct adenomas, and renal cell adenomas were observed in rats after dietary administration." Liver tumors were also observed in 100% of surviving females and 16% of males after dietary administration to rats for 90 weeks. In another study, increased incidence of parathyroid adenomas and adrenal pheochromocytomas were observed in male and female rats and liver neoplastic nodules in females of the Ei generation in a two-generation feeding study. 

US Army HMX 14 Day Toxicity Study in Mice and Rats by Dietary Administration. Ft. Detrick, MD, Research and Development Command, US Army Medical Bioengineering Research and Development Laboratory (authored by Greenough RJ, McDonald P), 1985... 

CUT (Chemical Industry Institute of Toxicology) Chronic Dietary Administration of Maleic Anhydride—Final Report, CUT Docket No. 114N3. Research Triangle Park, NC, 1983... 

Freundenthal RI, Thake DC, Baron RL Project Summary-Carcinogenic Potential of Rotenone Subchronic Oral and Peritoneal Administration to Rats and Chronic Dietary Administration to Syrian Golden Hamsters, Health Effect Research Laboratory Report EPA-66/Si-81-037. Research Triangle Park, NC, US Environmental Protection Agency, 1981... 

The lARC has noted, however, that thiram can react with nitrite under mildly acidic conditions, simulating those in the human stomach, to form N-nitrosodimethylamine, which is carcinogenic in a number of species." Dietary administration of 500 ppm thiram plus 2000ppm sodium nitrite for 2 years caused a high incidence of nasal cavity tumors in rats vs. no tumors in controls or in animals given only one compound. "... 

Renal function impairment Renal failure or dialysis patients may require smaller doses closely supervise to prevent cardiac failure or exacerbation of renal failure. Carcinogenesis Dietary administration of minoxidil to mice for up to 2 years was associated with an increased incidence of malignant lymphomas in females at all dose levels (10, 25, and 63 mg/kg/day) and an increased incidence of hepatic nodules in males (63 mg/kg/day). 

Selective COX-2 inhibitors have also been shown to prevent early and late forms of colorectal neoplasia in rat models. Reddy et al. showed that administration of celecoxib inhibited aberrant colonic crypt foci (ACF) induction and multiplicity by about 40-49% in an azoxymethane-induced ACF rat model (81). Later the same investigators also showed that dietary administration of celecoxib can inhibit both the incidence and multiplicity of colon tumors by about 93 % and 97 %, respectively in the same rat model (82). Other researchers reported similar results with the Min mouse model (52). There is little data on human clinical trials with selective COX-2 inhibitors for colorectal tumor prevention. Recently Steinbach et al. conducted a double-blind, placebo-controlled study with 77 patients with FAP, and reported that treatment with celecoxib, a selective COX-2 inhibitor, for 6 mo led to a significant reduction (28%) in the number of colorectal polyps in these patients (50). Collectively, COX-2 nonspecific or specific NSAIDs appear to have chemopreventive activity against colorectal cancer development. Selective... 

Dietary administration is not recommended, except for materials of low toxicity and for which gavage administration is not practical. Rabbits generally have very variable food consumption, and dietary administration is not suitable. Inhalation dosing is appropriate for some substances both whole body and nose only exposure are possible for teratology studies (10) and it is recommended that the same exposure method is used as in previous toxicity studies. 

The developmental studies are intended to provide information on any adverse effects of the food additive on pregnant women and their developing concepms. The study designs used are identical to those used to assess the prenatal toxicity of chemicals, except that dietary administration is preferred over gavage dosing. 

Cinnamaldehyde Cinnamomum cassia) is a potent inducer of apoptosis via ROS generation, thereby inducing mitochondrial permeability, depletion of intracellular thiols, activation of caspase-3 and DNA fragmentation [364]. Farnesol was also found to initiate apoptotic cell death [312, 318, 365], while other studies showed that dietary administration of cinnamaldehyde significantly inhibited pulmonary tumorigenesis in mice [366]. 

Dietary consumption (30 g/kg diet) of 11 g/kg bw per day by female B6C3Fi mice and 3 g/kg bw per day by female Fischer 344 rats for up to 13 weeks was not associated with lethality, although body weight gain was diminished (Lake et al., 1997). Similar dietary administration (15 or 30 g/kg diet) did not affect survival in studies of eight weeks and two years duration (National Toxicology Program, 1980). 

Fig. 1.1. Limonoids isolated from the seeds of Swietenia humilis and their effect on adult emergence of European corn borer following dietary administration at 50 ppm. CON, control T, tenulin (toosendanin Fig. 1.2) n = 30.

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