Abraham Goldberg

A retrospective analysis of blood-lead in mentally retarded children.

Blood-lead concentrations were measured retrospectively in the blood contained on cards used for testing for phenylketonuria in the first two weeks of life. Cards which belonged to 80 of a group of 77 children with mental retardation of unknown aetiology and 77 controls were identified. Of 77 usable cards, 41 were from mentally retarded children and 36 were from controls; 24 mental-retardation/control pairs were found. There was a highly significant trend towards higher blood-lead concentrations in the mentally retarded children. Water-lead concentrations in the maternal home during pregnancy correlated with blood-lead concentrations in the mentally retarded children. These results reinforce the probable association between lead exposure during pregnancy and the development of mental retardation of otherwise unknown aetiology.

Acute ethanol ingestion and haem biosnthesis in health subjects

Abstract. The effects of acute ethanol ingestion on the activities of the enzmes of haem biosnthesis in peripheral blood cells have been monitored in eight health subjects. The mitochondrial enzmes delta‐aminolaevulinic acid (ALA) snthase, coproporph‐rinogen oxidase and ferrochelatase were measured in leucoctes and the ctosolic enzmes ALA dehdratase, porphobilinogen (PBG) deaminase and uroporphrinogen decarboxlase in erthroctes. Ingestion of 1–316 mol ethanol resulted in increased activit of the rate‐controlling enzmes ALA snthase and PBG deaminase and decreased activit of the other four enzmes. There was also increased urinar excretion of coproporphrin. These observations ma be relevant to the biochemical mechanisms involved in the ethanol‐related conditions, sideroblastic anaemia, cutaneous hepatic porphria and hepatic siderosis.

ENZYME ABNORMALITIES IN THE PORPHYRIAS

Evidence is presented that each of the porphyrias represents a different inborn error of metabolism in haem biosynthesis. Control of the pathway takes place by feedback repression and inhibition by haem of delta-aminolaevulinic-acid synthase. It is suggested that insituations where the activity of this enzyme is derepressed, prophobilinogen deaminase represents a secondary control step.

PREGNANCY AND THE ACUTE PORPHYRIAS

An analysis is presented of the obstetric histories of 50 women with acute porphyria, comprising 39 with acute intermittent porphyria, 3 with variegate porphyria and 8 with hereditary coproporphyria. Fifty‐four per cent of the women with acute intermittent porphyria had an acute attack of porphyria in pregnancy and/or the puerperium. Only one maternal death was recorded. One patient with variegate porphyria and two with hereditary coproporphyria had an attack related to pregnancy. The total fetal wastage was 13 per cent. The babies born to mothers with acute intermittent porphyria, who experienced an acute attack during pregnancy, were smaller than those in which no such attack occurred (P<0·001). In 13 non‐porphyric primigravidae there was a rise in urinary excretion of 8‐aminolaevulinic acid, porphobilinogen and coproporphyrin up to the 28th week of gestation. It is probable that pregnancy has some deleterious effects in acute porphyria but the prognosis of the porphyric pregnancy is much better than the literature suggests.

The percutaneous absorption of lead-203 in humans from cosmetic preparations containing lead acetate, as assessed by whole-body counting and other techniques

Abstract The percutaneous absorption of lead from two hair-darkening cosmetic preparations containing lead acetate has been measured by radioisotopic tracer techniques, using lead-203 acetate, in eight normal human male subjects. Spiked preparations were applied in fluid and dried forms to each subjects forehead (with periods of 1 month between each application) and the quantity of lead absorbed was calculated from blood counts, whole-body counts and urine radioactivity. Results were normalized for each subject by administration of an iv tracer dose of lead-203 chloride, from which absorption was calculated. It was found that absorption of lead through the skin was essentially zero, with results ranging between 0 and 0·3% of the dose applied to whole skin. Slight absorption was found when the skin was broken. The potential hazard of the use of such cosmetic preparations is therefore considered to be insignificant.

Hepatic drug metabolism and haem biosynthesis in lead-poisoned rats.

1 Pretreatment of rats with intraperitoneal injections of lead was shown to result in a depression of the microsomal mixed function oxidase system, as assessed by a decrease in hepatic microsomal P‐450 and b5 content and by a decrease in the activity of the enzymes aniline hydroxylase and aminopyrine demethylase. Lead had a more marked effect on cytochrome P‐450 than b5. 2 The activity of the rate‐limiting enzyme of haem biosynthesis, δ‐aminolaevulinic acid synthase, was inversely correlated with the microsomal cytochrome P‐450 content. 3 The activity of the haem biosynthetic enzymes δ‐aminolaevulinic acid dehydratase, coproporphyrinogen oxidase and ferrochelatase were decreased by increasing lead pretreatment. 4 The activity of the haem catabolic enzyme, haem oxygenase, was increased by lead pretreatment.

The effects of industrial lead poisoning on cytochrome P450 mediated phenazone (antipyrine) hydroxylation.

SummaryIn a group of ten male adults admitted to hospital with clinical symptoms of lead exposure, phenazone elimination rates, blood δ-amino-laevulinic acid dehydratase (ALA.D) activity, blood lead levels and haemoglobin were measured. Investigations were carried out before, immediately after and again at least 12 weeks after cessation of CaEDTA (sodium calcium edetate) chelation therapy. Following chelation, phenazone elimination rates were increased as assessed by a decrease in half life and increase in clearance. This was significant, both immediately after and 12 weeks after cessation of chelation therapy. The change in rate of phenazone metabolism was associated with improved clinical status, with lowered blood lead levels and raised haemoglobin and ALA.D activity. The results of the study suggest that the depression in phenazone elimination in lead intoxication is possibly due to depressed hepatic cytochrome P450 levels.

The biosynthesis of haem in congenital (erythropoietic) porphyria.

Abstract 1. 1. The enzymes of haem biosynthesis have been measured in peripheral blood in two patients aged 6 and 20 yr with congenital (erythropoietic) porphyria. 2. 2. Excessive activity of leucocyte δ-aminolaevulinic acid synthase was found in both patients. 3. 3. The activity of erythrocyte porphobilinogen deaminase was elevated and coupled with a lowered activity of uroporphyrinogen cosynthase, which resulted in excessive production of Series l isomer porphyrin. 4. 4. This was confirmed by isomer analysis of urine which showed an excess in both of coproporphyrin 1. 5. 5. Faecal porphyrin analysis demonstrated excessive quantities of ‘X’ porphyrin in one patient in common with other photosensitizing porphyrias. 6. 6. These results confirm that the primary control of haem biosynthesis in congenital porphyria is at the level of δ-aminolaevulinic acid synthase. with a secondary control point at the level of porphobilinogen deaminase.

The association between lead concentrations in teeth and domestic water lead concentrations

Tooth lead levels have been measured in 109 children living in Glasgow. A significant association has been demonstrated between molar tooth lead concentrations and domestic drinking water lead concentrations. Tooth lead concentrations were found to be greater the longer a child had liver in older housing with lead plumbing during foetal life and following birth. Tooth lead concentrations were also found to be age-related although no difference with respect to social class could be found.

The contribution of drinking water lead to maternal blood lead concentrations

The association between domestic water lead concentrations and blood lead concentrations has been examined in 232 mothers at delivery. The blood lead was found to vary significantly with the cube root of the water lead. This association was stronger for first flush water lead rather than for running water lead. This study emphasises the danger to mothers and to their children of environmental lead over-exposure in areas of soft acid plumbosolvent water.