Evaluating hazardous air pollutants in Australia.

Hazardous air pollutants (HAPS) have been evaluated for their health and environmental significance on a targeted and campaign basis in Australia until recently. Individual States and Territories have been undertaking targeted monitoring studies and have numerous control strategies aimed at controlling HAPS emissions with the focus largely on volatile organic compounds (VOCs), polycyclic aromatic hydrocarbons (PAHs) and selected heavy metals, with some limited work on exposure assessment. There has been little evaluation of the potential health or environmental effects of the monitored concentrations of these substances and few toxicological or epidemiological studies have been conducted-none in the community setting in Australia. Moreover, there has not been an agreed method for assessing risks from HAPS in ambient air, with different jurisdictions utilising different international benchmarks. Recently, the National Environmental Health (EnHealth) Council commenced developing a risk assessment methodology, which is being used in the development of ambient air quality guidelines for selected HAPS in Western Australia. In 1999, the Commonwealth Government established the Living Cities-Toxics Program, designed to assess the state of knowledge on HAPS in Australia with the aims of identifying and prioritising HAPS, identifying information gaps and informing the development of national air quality standards and national management strategies. The Commonwealth Government commenced a number of projects in 2000 to progress these aims.

Carcinogen risk assessment. Can we harmonise?

Harmonisation of risk assessment (RA) is one of the priorities for sound chemical management set by Chapter 19, Agenda 21 of the United Nations Conference on the Environment and Development (UNCED) 1992 Earth Summit. The benefits of harmonisation are self evident and include transportability and consistency of RA outcomes, transparency and efficiency of process, and credible science. The outcomes of carcinogen RA are a description or classification of the carcinogenic hazard, the conditions under which cancers may be induced, and an estimate of a dose or exposure which poses a minimal, or otherwise defined, risk in exposed human populations. Weight-of-evidence based systems which classify carcinogenic hazards are part of, but do not substitute for, the risk assessment process. Carcinogen RA is based on assessment of appropriate toxicological and exposure data sets, which may have much in common. However, national policy frameworks can differ to the extent that RA outcomes may be quite different for the same chemical(s). Historically, differences in science policy have been greater for cancer RA compared to other toxic endpoints, with a tendency to differentiate cancer RA on the basis of presumed mechanism (i.e. genotoxic or non-genotoxic) and relevance to humans (some carcinogenic responses in animals may be considered not relevant for human RA). Significant strides towards harmonisation are being made, with reassessment of some national policies and participation in international harmonisation programmes, such as the ones being managed by the International Programme for Chemical Safety (IPCS). Alternative approaches to quantitative carcinogen RA are being considered which are more amenable to harmonisation, and one such approach being developed in Australia in connection with contaminated sites will be discussed.

Natural bone marrow transplantation in cattle with Pompe's disease.

Adding acid alpha-glucosidase to cultures of Pompe's disease muscle has resulted in enzyme uptake and reduction in concentration of glycogen. However, bone marrow transplantation has been unsuccessful as a treatment. Immune rejection may have contributed to this failure. Twin calves share a placenta and carry lymphoreticular cells of each other's type, they become lymphoreticular chimeras in utero and immune rejection does not occur. One natural and three sets of twins produced by embryo transfer were studied in Pompe's disease cattle. Chimerism persisted throughout life and the situation was analogous to a transplant of histocompatible bone marrow stem cells. The activity of acid alpha-glucosidase in leucocytes and in biopsies of the semitendinosus muscle and the mean activity in diaphragm, spleen and lymph node obtained after death from affected twins were significantly higher than in single affected calves. Glycogen concentration was lowered in liver, spleen and lymph node but not in muscles. The affected twins showed clinical signs and changes in muscle similar to those seen in affected single calves. It is concluded that bone marrow transplantation is unlikely to be a successful treatment for Pompe's disease.

Bovine generalised glycogenosis type II. Uptake of lysosomal alpha-glucosidase by cultured skeletal muscle and reversal of glycogen accumulation.

acid alpha-glucosidase (EC 3.2.1.20) was purified from fetal bovine muscle by affinity chromatography on concanavalin A and Sephadex G-100 and added to the culture medium of mature muscle cultures from animals affected by glycogenosis type II. The enzyme activity in homogenates of treated cultures was significantly increased within 4 h of the addition of enzyme, was maximal by 18 h and the internalised activity was stable for at least 48 h after the removal of the enzyme from the culture medium. The acid alpha-glucosidase activity was internalised with an uptake constant of 300 nM and a Vmax of uptake of 133 nmol/h per mg protein. The glycogen concentration in affected cultures treated with exogenous acid alpha-glucosidase for 24 h had decreased by 20% and after a further 24 h of culture was comparable to the concentration observed in cultures from non-affected animals.

Bovine glycogenosis type II. Biochemical and morphological characteristics of skeletal muscle in culture.

The biochemical and morphological properties of cultured skeletal muscle from calves born into a herd of cattle, which are heterozygous for glycogenosis type II, were studied over 17 days. Muscle was cultured by a modification of the explant technique in which the mononucleated cells that grew from the explants were subcultured. Skeletal muscle from animals up to 15 months of age grew in culture to produce mature, cross-striated and spontaneously contractile myotubes. The creatine kinase activity was 310 (+/- 45.4) mU/mg protein on day 7 when fusion was complete, and 210 (+/- 15.1) mU/mg protein on day 17 of culture. Mature muscle cultures from animals affected by glycogenosis type II showed the characteristic biochemical and morphological abnormalities previously observed in vivo. Acid alpha-glucosidase activity was absent whereas the activities of neutral alpha-glucosidase, lysosomal alpha-mannosidase and creatine kinase were the same as in cultures of unaffected muscle. The concentration of glycogen was higher in cultured affected muscle than in cultured unaffected muscle. On days 7, 9 and 17 of culture the glycogen concentrations were 66.7 (+/- 2.7), 89.0 (+/- 5.5) and 120.3 (+/- 34.2) micrograms/mg protein respectively in affected muscle and 51.8 (+/- 3.6), 59.9 (+/- 5.4) and 55.4 (+/- 1.0) micrograms/mg protein respectively in non-affected muscle. Electron microscopic studies showed that the glycogen accumulated within the lysosomes. These results indicate that bovine glycogenosis type II is expressed in tissue culture since the cultured skeletal muscle from affected animals shows the same abnormalities as skeletal muscle in vivo.

Adenosine 3':5'-monophosphate in perinatal rat liver. Ontogeny and response to hormones.

Developmental changes in the concentration of adenosine 3':5'-monophosphate (cyclic AMP) and the effects of glucagon and epinephrine were studied in the perinatal rat liver. Hepatic cyclic AMP concentration doubled during the last day of gestation. After birth, the cyclic AMP concentration continued to increase and maximal levels were observed on the fifth postnatal day. Surgical delivery of foetuses on days 20, 21 and 22 of gestation resulted in a rapid increase in cyclic AMP concentration. Maximal concentrations were reached within one hour of delivery in the day-21 and day-22 foetuses. However with surgically delivered day-20 foetuses, the cyclic AMP concentration increased for a least two hours. Glucagon and epinephrine increases the hepatic cyclic AMP concentration in rats delivered surgically on days 20, 21 and 22 of gestation and in postnatal rats. Maximal stimulation by epinephrine was observed in 2-day-old rats. Maximal stimulation by glucagon was observed in 10-day-old rats. The results support the hypothesis that cyclic AMP is the intracellular effector for the synthesis of some enzymes in the perinatal rat. The cyclic AMP concentration in the perinatal rat liver in vivo appears to be controlled by changes in the relative concentrations of plasma glucagon and insulin.