Further development of mathematical description for combined toxicity: A case study of lead-fluoride combination.

In this article, we check and develop further some postulates of the theory and mathematical modeling of combined toxic effect that we proposed earlier [1]. To this end, we have analyzed the results of an experiment on rats exposed during 6 weeks to repeated intraperitoneal injections of lead acetate, sodium fluoride or both. The development of intoxication was estimated quantitatively with 54 functional, biochemical and morphometric indices. For mathematical description of the effect that lead and fluorine doses produced alone or in combination, we used a response surface regression model containing linear and cross terms (hyperbolic paraboloid). It is shown that the combination of lead and fluoride features the same 10 types of combined effect that we found previously for the lead and cadmium combination. Special attention is given to indices on which lead and fluorine produce an opposite effect.

Some considerations concerning the theory of combined toxicity: a case study of subchronic experimental intoxication with cadmium and lead.

Rats were exposed intraperitoneally (3 times a week up to 20 injections) to either Cadmium and Lead salts in doses equivalent to their 0.05 LD50 separately or combined in the same or halved doses. Toxic effects were assessed by more than 40 functional, biochemical and morphometric indices. We analysed the results obtained aiming at determination of the type of combined toxicity using either common sense considerations based on descriptive statistics or two mathematical models based (a) on ANOVA and (b) on Mathematical Theory of Experimental Design, which correspond, respectively, to the widely recognised paradigms of effect additivity and dose additivity. Nevertheless, these approaches have led us unanimously to the following conclusions: (1) The above paradigms are virtually interchangeable and should be regarded as different methods of modelling the combined toxicity rather than as reflecting fundamentally differing processes. (2) Within both models there exist not merely three traditionally used types of combined toxicity (additivity, subadditivity and superadditivity) but at least 10 variants of it depending on exactly which effect is considered and on its level, as well as on the dose levels and their ratio.

Attenuation of subchronic formaldehyde inhalation toxicity with oral administration of glutamate, glycine and methionine.

Inhalation exposure of outbred female white rats (initial age about 4 months) to formaldehyde vapours (12.8 ± 0.69 mg/m(3)) 4h per day, 5 days per week during 10 weeks induced statistically significant changes in some indices characterizing differential WBC count, functional status of the central nervous system and liver, redox and porphyrin metabolisms, bone marrow micronuclei count as well as free amino acid spectrum of the blood serum. The development of intoxication was accompanied by increased urinary excretion of formaldehyde, formic acid and methanol. Daily oral administration of glutamate (150-180 mg), glycine (12 mg) and methionine (50mg) in combination rendered all of the formaldehyde's toxic effects reduced. This administration also caused a significant increase in the ratio between the rates of excretion of formic acid and non-metabolized formaldehyde. This shift supposedly reflects activation of oxidative detoxifying biotransformation of formaldehyde. Taking into consideration that the combination of amino acids used in this study proved innocuous in protectively effective doses, the administration in this combination may be recommended to humans exposed to high levels of formaldehyde in workplace or ambient air.

Toxicity of monazite particulates and its attenuation with a complex of bio-protectors.

BACKGROUND: Workers employed on mining, processing and storage of monazite are at risk of exposure to dust with expected adverse health effects. OBJECTIVES: To study the adverse health effects of monazite particles in experiments on rats and to test the possibility of attenuating these effects. METHODS: Outbred white rats were injected intratracheally with a suspension of ground monazite concentrate (MC) in order to investigate the cellular response of the lower airways 24 hours later and the organism's status 6 months after the injection. The bio-protective complex (BPC) tested in these experiments consisted of glutamate, an iodine preparation, methionine, a polyvitamin-polymineral composition, and/or "Eicosavitol" (fish oil preparation rich in PUFA, predominantly of the omega 3-group). Bio-protectors were administered together with the rat food and drink daily for one month before the MC injection in the short-term experiment, or over 6 months after such injection in the long-term experiment. RESULTS: MC induced manifestations of its cytotoxicity, fibrogenicity and systemic toxicity as well as genotoxicity. The tested BPC attenuated virtually all these effects. Although a similar protective potential of "Eicosavitol" against almost all of them was lower compared with that of BPC, combining BPC with "Eicosavitol" provided, as a rule, the greatest protective effect. CONCLUSION: It may be assumed that the many-sided adverse effects of MC on the organism is due, at least partially, to the presence in its composition of not only rare earth elements but also of natural radioisotopes of the thorium and uranium families. The combination of the bio-protectors tested was highly effective and may be recommended for administering in periodic preventive programmes to exposed workers.