Human & Experimental Toxicology

Considerable research has been conducted to identify possible mechanisms of the carcinogenicity of methylene chloride in rodents, and to ascertain whether the observed increased incidences of liver and lung tumours in mice exposed to this substance, are relevant in assessing the potential hazards and risks to human health. On the basis of a study that purported to show qualitative differences between murine and human tissues, in the subcellular localization of the Theta-class glutathione S-transferase enzyme responsible for converting methylene chloride to a putative highly unstable, but reactive genotoxic metabolite, it was suggested that the mouse is an inappropriate model for human health risk assessment. However, other studies conducted in vitro with intact cells do not support the hypothesis that a putatively reactive metabolite of methylene chloride must be generated only within the nucleus in order to be able to interact with genomic DNA. Moreover, investigations employing semi-quantitative methods of mRNA hybridization are not convincing in identifying the subcellular localization of active Theta class glutathione S-transferase, and do not support the hypothesis of the differential subcellular localization of this enzyme within the nucleus of mouse, but not human cells. There is therefore, insufficient evidence to support the view that qualitative differences between humans and mice in the subcellular distribution of Theta-class glutathione S-transferase, renders carcinogenicity studies conducted with mice irrelevant in human hazard identi-fication and risk assessment.

Hormonal imprinting is provoked perinatally by the appropriate hormone on its receptor, causing a life-long adjustment of the connection between the two participants. Faulty imprinting is caused by the presence of molecules similar to the hormone in this critical period, which results in a persistent alteration of the receptor. In the present experiment the transgenerational imprinting effect of a steroid-like environmental pollutant, benzpyrene, on the receptor binding capacity of filial thymic dexamethasone and uterine estrogen receptors was studied. The receptor density (B_max) of the thymic glucocorticoid receptors of the males was reduced up to the third (F₂) generation. In females this reduction was observed only in the F₁ generation of treated animals. There was no change in receptor affinity (K_d). Uterine estrogen receptors were not subjected to transgenerational imprinting. The experiments demonstrate (1) the possibility of the transgenerational transmission of imprinting effect, (2) the differences of steroid receptors in different organs, and (3) the differences of male's and female's reactions from this aspect. The results call attention to the dangers of perinatal aromatic hydrocarbon exposition to the progeny generations.

N-(2-hydroxypropyl)methacrylamide (HPMA) copolymer-doxorubicin (PK1) is a novel polymeric anticancer agent containing doxorubicin (approximately 8 wt%) bound to the polymer backbone via a Gly-Phe-Leu-Gly peptidyl linker. The approximate LD₅₀ of PK1 in MF1 mice after a single i.v. injection was 63 mg/kg (doxorubicin-equivalent). Single doses of PK1 were administered to MF1 mice at 22.5 or 45 mg/kg and blood samples taken on days 3, 7 and 14 for haematological examination and clinical chemistry. At day 14 all animals were sacrificed for necropsy. In a multiple dose study, PK1 was administered i.v. to MF1 mice or Wistar rats (20 animals per group) weekly for five consecutive weeks at doses of 12.0 or 22.5 mg/kg (mice) or 3 and 5 mg/kg (rats). After 31 days 10 animals from each group were sacrificed for necropsy and the remainder were sacrificed after 59 days. Blood samples were taken 3 days after administration of each dose and at the end of the experiment, and urine samples were collectedonthe day prior to sacrifice.Mortality inthe single dose mouse and multiple dose rat studies was low. In the multiple dose mouse study 4/10 animals were killed in extremis before the scheduled day 31 and all animals died before day 37. PK1 induced a reduction in WBC and platelets in rats and mice shortly after treatment and RBC at later times, and in the single dose study alanine and aspartate aminotransferase levels were elevated at higher doses. Liver damage was seen only in rat tissue during histological examination. Other histological changes induced by PK1 include thymic and testicular atrophy, bone marrow depletion gastrointestinal tract changes and in the multiple dose study an increase in nuclear size in the proximal tubules of the kidney (although no changes in urine were seen). Recovery from these effects was seen in rats at 59 days. A PK1 dose of 20 mg/m² (doxorubicin equivalent) was recommended as a safe dose for the start of Phase I clinical trials.

Exposure to zinc fume may cause metal fume fever, an acute reaction characterized by an invasion of neutrophils into the airways. This investigation was conducted to examine the possibility that Zn²⁺ and ZnO might stimulate the formation of oxygen radicals by human neutrophils. Luminol-amplified chemiluminescence (CL) was monitored during 2 h from human neutrophils exposed to Zn²⁺or ZnO. The response was compared to that of other metal ions and to that of endotoxin and phorbol myristate acetate (PMA). Zn²⁺ (6-50 mM) gradually caused a 2-6-fold increase of CL that reached an optimum after 70-80 min. By contrast, Cd²⁺, Cr²⁺, Cr³⁺, Fe²⁺, Fe³⁺, Ni²⁺ or Co²⁺ in corresponding concentrations did not increase the CL. Similar to Zn²⁺, endotoxin (40-640 mg/ml) caused a 2-5-fold increase of CL with an optimum after 70 min, and endotoxin (40 mg/ml) together with Zn²⁺ (50 mM) synergistically increased the CL. ZnO (12-100 mg/ml) also augmented CL, with a 1.5-5-fold increase at 25-100 mg/ ml ZnO but with a time response similar to that found after PMA stimulation, in which CL peaked after 20-40 min incubation. Both Zn²⁺- and ZnO-induced CL was inhibited by manoalide, a phospholipase A₂ inhibitor, with IC₅₀ of 0.25 mM and 0.66 mM respectively. These results indicate that Zn²⁺ and ZnO both stimulates oxygen radical formation in human neutrophils and that this might contribute to the pathogenesis of zinc fume fever.

1 All petroleum based products are highly complex chemical mixtures. Although almost exclusively composed of hydrocarbons, the composition varies with the crude oil source.

2 Their toxicity for man is generally low but there are exceptions. Although irritancy and sensitization to specific ingredients may be demonstrated in animals, animal experiments are not a reliable indicator of sensitization potential in man.

3 Both product complexity and commercial considerations can make acceptable and meaningful compositional disclosures difficult. A nomenclature system exists which solves these problems.

4 Frame formulations would have some value to poisons centres dealing with petroleum product enquiries.

5 As legislation for the European Union is developed, the balance must be reached between disclosure of the (often confidential) precise chemical composition of products and a practical and useful composition for the guidance of users and medical personnel. This is a key issue with some petroleum products, mainly due to the additives used in them.

6 For several reasons, such as climatic conditions or logistics of supply, the various components, including additives, used in a branded product may vary because the final product composition is determined not by chemistry but by performance in service.

7 Lubricants may contain between 10 and 20% of additives; fuels contain additives only at parts per million levels. However, for both fuels and lubricants, toxicity from additives is rarely a matter of concern.

This preliminary study was designed in a trial to delineate the size of the problem of ochratoxicosis and its relation to genesis of lesions mounting to end stage renal disease (ESRD) or urothelial tumors in Egypt. This study comprised five groups of patients having renal diseases of different presentations; they are: patients with (ESRD) under conservative medical treatment (group 1), patients with (ESRD) under treatment with regular hemodialysis (group 2), renal allograft recipients (group 3), patients with nephrotic syndrome (group 4) and patients with urothelial tumors (group 5). In addition, two reference groups: potential related donors for renal transplantation (group 6) and healthy control with negative family history of renal disease (group 7).

For all groups, laboratory, radiological and histopatho-logical evaluation of kidney status were carried out coupled with determination of ochratoxin A level in serum, in urine and in biopsy specimens of patients with urothelial tumors.

High ochratoxin serum levels were found in patients with ESRD (groups 1 and 2) (P50.01), higher serum levels were detected in the group without dialysis (group 1) in comparison with the reference groups possibly due to ochratoxin. A clearance by dialysis. Ochratoxin A was detected in serum and urine of renal transplant recipients (group 3) (P50.01) and especially higher levels were found in patients with nephrotic syndrome (group 4) (P50.001). For the group with urothelial tumor (group 5), positive serum, urine and tissue biopsy specimens for ochratoxin levels were found (P50.01).

The results could lead to the conclusion that ochratoxin A could be correlated to the genesis of renal disease leading to (ESRD) or causing urothelial cancer. A thorough and in depth study of the problem of ochratoxicosis and renal disease causation in Egypt is now recommended.