Cadmium, mercury and the kidney
2
Information section--Fd almost no loss of coating thickness in the process. A typical UV ink is essentially a multifunctional acryl- ate mixed with a chemical system capable of gener- ating free radicals on demand. These inks first came to the attention of the dermatologist when the acryl- ates that were then favoured pentaerythritol tri- acrylate (PETA) and trimethylolpropane triacrylate (TMPTA), for example turned out to be sensitizers capable of producing contact dermatitis in any work- force that might abuse them (Cited in F.C.T. 1978, 16, 297; ibid 1979, 17, 313). There has been a tendency in recent years for the low-molecular-weight acrylates to be replaced in many formulations by the acrylated oligomers, based for example, on the epoxides or polyesters. However, it would seem that even the present-day UV inks may still be carrying an immu- nological cross. The epoxyacrylates, which fairly quickly joined the ranks of human sensitizers (ibid 1978, 16, 297) have now been joined by the urethane acrylates (Nethercott et al. Br. J. ind. Med. 1983, 40, 241). Plastic food containers printed on the outside with UV inks in an offset printing process were the cause of an outbreak of dermatitis in one workforce. Even though a number of the tasks in the plant involved contact with the uncured inks, gloves were not a common feature of the workers" lifestyle. Out of eight press operators and two foremen working with the presses, seven developed dermatitis. A clinical diag- nosis of irritant contact dermatitis was made for one individual and was tentatively attributed to the mod- erate irritant, TMPTA, while allergic contact der- matitis was diagnosed in the reamining six. In order to identify the allergen responsible, these six workers were subjected to 48-hr closed-patch tests using methyl methacrylate, toluene diisocyanate (TDI) and a number of acrylates a urethane acrylate, [bur epoxy acrylates, PETA, TMPTA and hexanediol diacrylate applied in petrolatum (or, for TDI only, in acetone) at concentrations of 1'!~0for the epoxies and methyl methacrylate and 0.1~I,, for the rest. All the test chemicals (in these vehicles and at the test concentrations) had been shown to be non-irritant in a preliminary screening test using 20 volunteers. Five of the six workers studied experienced a moderate to severe reaction to the urethane acrylate, and in no instance was the reaction any less severe 48hr after removal of the patch. Two of those sensitized to the urethane compound reacted to one other acrylate, in one instance to PETA, a material apparently present in a previous ink formulation, and in the other to one of the four epoxies. Concurrent sensitization rather than cross reaction was felt to be the most likely cause of the double reactions. In the worker not responsive to the urethane acrylate patch, there was still support for the clinical diagnosis of allergenicity because sensitization occurred to Chem. Toxic'. Vol. 22, no. 6 493 TMPTA, an acrylate used in the plant to reduce ink viscosity. The investigators went on to explore the urethane acrylate's local toxicity in laboratory animals. In a standard Draize test in the rabbit, the neat liquid exhibited only a mild dermal irritancy, illustrating again the lack of correlation between irritancy and sensitization, the allergenic potency of the urethane was compared with that of methyl methacrylate, TDI and a number of low-molecular-weight acrylates in a guinea-pig study using a protocol based on that of Magnusson & Kligman (Allergic Contact Dermatitis in the Guinea-Pig, Charles C. Thomas, Springfield, 1970). The maximum concentrations of the test com- pounds that caused no severe injury or systemic toxicity when injected intradermally (in propylene glycol) and no irritant reaction following a 24-hr dermal application in petrolatum were determined. Attempts were then made to induce a sensitized state in guinea-pigs in two stages, administration of the test compound intradermally in two injections given on a single day at different body sites being followed 1 wk later by a 48-hr dermal exposure. Except in the case of TDI, which was tested in a single concentration, multiple concentrations up to the maximum levels found to be acceptable in the preliminary experiments were examined. All the tested compounds showed some evidence of aller- genicity when the guinea-pigs were challenged 2 wk after the topical-induction exposure. TMPTA, hex- anediol diacrylate, tripropylene glycol diacrylate, TDI and the urethane acrylate exhibited roughly similar immunological activities: in each case the intradermal concentration capable of inducing a sen- sitized state in half of the treated animals lay in the range 2.5 6"~, while the corresponding concentration for the methacrylate was 14.8~(, . PETA was by far the most potent sensitizer, a 501~; incidence of in- duction being achieved by a concentration of 0.005!~0. Previous maximization studies of an epoxy acrylate had indicated a sensitizing potential similar to or slightly higher than that of the urethane acrylate (Nethercott, Br. J. Derm. 1981, 104, 697). To complete their studies, Nethercott et al. (Ioe. tit.) checked on the purity of the technical-grade urethane acrylate supplied by the manufacturers of the printing ink, to see whether low-level con- taminants were responsible for the observed aller- genicity. Free isocyanate was not detectable using an infrared spectrophotometric method shown to be sensitive to 0.6'!,i free isocyanate. The urethane acryl- ate gave two major peaks on HPLC analysis, neither of which corresponded to any of the peaks seen with TMPTA, hexanediol diacrylate or PETA. The HPLC trace also confirmed that no free acrylic acid was present in the urethane acrylate. CADMIUM, MERCURY AND THE KIDNEY Wild animals can accumulate heavy metals, either from natural sources or as a result of pollution of their habitat. For instance, elevated levels of cad- mium (Cd), lead and zinc have been found in the bodies of London pigeons (Cited in F.C.T. 1982, 20, 240). High levels of Cd and mercury (Hg) have adverse effects on the kidneys of animals and humans (ibid 1975, 13, 468; ibid 1979, 17, 84: ibid 1982, 20,
Transcript of Cadmium, mercury and the kidney
Information section--Fd
almost no loss of coating thickness in the process. A typical UV ink is essentially a multifunctional acryl- ate mixed with a chemical system capable of gener- ating free radicals on demand. These inks first came to the attention of the dermatologist when the acryl- ates that were then favoured pentaerythritol tri- acrylate (PETA) and trimethylolpropane triacrylate (TMPTA), for example turned out to be sensitizers capable of producing contact dermatitis in any work- force that might abuse them (Cited in F.C.T. 1978, 16, 297; ibid 1979, 17, 313). There has been a tendency in recent years for the low-molecular-weight acrylates to be replaced in many formulations by the acrylated oligomers, based for example, on the epoxides or polyesters. However, it would seem that even the present-day UV inks may still be carrying an immu- nological cross. The epoxyacrylates, which fairly quickly joined the ranks of human sensitizers (ibid 1978, 16, 297) have now been joined by the urethane acrylates (Nethercott et al. Br. J. ind. Med. 1983, 40, 241).
Plastic food containers printed on the outside with UV inks in an offset printing process were the cause of an outbreak of dermatitis in one workforce. Even though a number of the tasks in the plant involved contact with the uncured inks, gloves were not a common feature of the workers" lifestyle. Out of eight press operators and two foremen working with the presses, seven developed dermatitis. A clinical diag- nosis of irritant contact dermatitis was made for one individual and was tentatively attributed to the mod- erate irritant, TMPTA, while allergic contact der- matitis was diagnosed in the reamining six. In order to identify the allergen responsible, these six workers were subjected to 48-hr closed-patch tests using methyl methacrylate, toluene diisocyanate (TDI) and a number of acrylates a urethane acrylate, [bur epoxy acrylates, PETA, TMPTA and hexanediol diacrylate applied in petrolatum (or, for TDI only, in acetone) at concentrations of 1'!~0 for the epoxies and methyl methacrylate and 0.1~I,, for the rest. All the test chemicals (in these vehicles and at the test concentrations) had been shown to be non-irritant in a preliminary screening test using 20 volunteers.
Five of the six workers studied experienced a moderate to severe reaction to the urethane acrylate, and in no instance was the reaction any less severe 48hr after removal of the patch. Two of those sensitized to the urethane compound reacted to one other acrylate, in one instance to PETA, a material apparently present in a previous ink formulation, and in the other to one of the four epoxies. Concurrent sensitization rather than cross reaction was felt to be the most likely cause of the double reactions. In the worker not responsive to the urethane acrylate patch, there was still support for the clinical diagnosis of allergenicity because sensitization occurred to
Chem. Toxic'. Vol. 22, no. 6 493
TMPTA, an acrylate used in the plant to reduce ink viscosity.
The investigators went on to explore the urethane acrylate's local toxicity in laboratory animals. In a standard Draize test in the rabbit, the neat liquid exhibited only a mild dermal irritancy, illustrating again the lack of correlation between irritancy and sensitization, the allergenic potency of the urethane was compared with that of methyl methacrylate, TDI and a number of low-molecular-weight acrylates in a guinea-pig study using a protocol based on that of Magnusson & Kligman (Allergic Contact Dermatitis in the Guinea-Pig, Charles C. Thomas, Springfield, 1970). The maximum concentrations of the test com- pounds that caused no severe injury or systemic toxicity when injected intradermally (in propylene glycol) and no irritant reaction following a 24-hr dermal application in petrolatum were determined. Attempts were then made to induce a sensitized state in guinea-pigs in two stages, administration of the test compound intradermally in two injections given on a single day at different body sites being followed 1 wk later by a 48-hr dermal exposure.
Except in the case of TDI, which was tested in a single concentration, multiple concentrations up to the maximum levels found to be acceptable in the preliminary experiments were examined. All the tested compounds showed some evidence of aller- genicity when the guinea-pigs were challenged 2 wk after the topical-induction exposure. TMPTA, hex- anediol diacrylate, tripropylene glycol diacrylate, TDI and the urethane acrylate exhibited roughly similar immunological activities: in each case the intradermal concentration capable of inducing a sen- sitized state in half of the treated animals lay in the range 2.5 6"~, while the corresponding concentration for the methacrylate was 14.8~(, . PETA was by far the most potent sensitizer, a 501~; incidence of in- duction being achieved by a concentration of 0.005!~0. Previous maximization studies of an epoxy acrylate had indicated a sensitizing potential similar to or slightly higher than that of the urethane acrylate (Nethercott, Br. J. Derm. 1981, 104, 697).
To complete their studies, Nethercott et al. (Ioe. tit.) checked on the purity of the technical-grade urethane acrylate supplied by the manufacturers of the printing ink, to see whether low-level con- taminants were responsible for the observed aller- genicity. Free isocyanate was not detectable using an infrared spectrophotometric method shown to be sensitive to 0.6'!,i free isocyanate. The urethane acryl- ate gave two major peaks on HPLC analysis, neither of which corresponded to any of the peaks seen with TMPTA, hexanediol diacrylate or PETA. The HPLC trace also confirmed that no free acrylic acid was present in the urethane acrylate.
CADMIUM, MERCURY AND THE KIDNEY
Wild animals can accumulate heavy metals, either from natural sources or as a result of pollution of their habitat. For instance, elevated levels of cad- mium (Cd), lead and zinc have been found in the
bodies of London pigeons (Cited in F.C.T. 1982, 20, 240). High levels of Cd and mercury (Hg) have adverse effects on the kidneys of animals and humans (ibid 1975, 13, 468; ibid 1979, 17, 84: ibid 1982, 20,
494 Information section Fd
343; ibid 1983, 21, 232). Nicholson et al. (Nature, Lond. 1983, 3114, 633) examined the kidneys of sea- birds contaminated with Cd and Hg and compared them with those of birds from a relatively uncon- taminated colony. They also compared the lesions in the seabird's kidneys with those in the kidneys of starlings and mice that had been dosed with Cd or Hg.
Fulmar petrels and Manx shearwaters were cob lected from the St Kilda colony and had mean kidney concentrations of 100 200 mg Cd and 5 13 mg Hg/kg dry tissue. Nephrotoxic lesions were characterized by light and electron microscopy and were found to be very frequent in these birds. In contrast, such lesions were rarely seen in the kidneys of birds from the uncontaminated colony. Starlings and A,G mice were given subcutaneous doses of Cd e+ or Hg'- ' that resulted in kidney levels of Cd and Hg similar in magnitude to those in the St Kilda seabirds. Micro- scopic examination showed that the nephrotoxic le- sions that occurred in these dosed animals were similar in type and severity to those that had been observed in the kidneys of the St Kilda seabirds. Similarities between the three groups were also seen in biochemical changes in the kidney, such as changes in the elemental composition of the proximal tubules. However, all of the animals appeared outwardly healthy.
Nicholson et al. (lot. cir.) consider that there is cause for concern in their findings. They cite refer- ences (Friberg et al. Cadmium in the Environment, CRC Press, Cleveland, OH, 1974, p. 108; Hamilton et al. Sei. Total Em'ir. 1972, 1, 341) which indicate
Chem. Toxic. Vol. 22, no. 6
that the renal lesions observed in this study occurred at Cd concentrations of the same order as those found in Western adult human populations. Further- more potentially irreparable kidney damage (tu- bulorrhexis) and inflammation were observed at and below renal Cd concentrations (200mg/kg wet weight= >600mg/kg dry weight) that have pre- viously been considered to have no serious effects on kidney function in man (Tech. Rep. Ser. WId Hlth Org. 1972, 505, 23).
A later WHO report (Teeh. Rep. Ser. WId HIth Or~,. 1980, 647, 30) cites the unpublished 1977 report of a WHO Task Group which concluded, on the basis of evidence from autopsy studies, that the critical level of Cd in the renal cortex for the appearance of proteinuria was between 100 and 300mg/kg wet weight. Roels el al. (Lancet 1979, I, 221) investigated workers occupational exposed to Cd and determined the critical level to be between 200 and 250 mg/kg wet weight. However, it has been suggested in a recent report (Evaluation of the Relationships between Cad- mium Exposure and Indicators ~?/ Kidney Function) prepared by M. Hutton, Monitoring and Assessment Research Centre, Chelsea College, University of Lon- don (MARC Report No. 29, 1983: pp. 46, £4.00), in which the relationship between Cd exposure and indicators of kidney function was evaluated using data from several Cd-exposed human populations, that the biological limit for Cd in urine (5 l~g Cd/g creatinine) proposed by the WHO study group in 1980 (lot. cir., p. 35) may in fact be unnecessarily stringent.
ASBESTOS AND LIPID PEROXIDATION
The importance of free radicals in carcinogenesis is a subject of recent interest. The role of active oxygen and the hydroxyl radical in radiation carcinogenesis has been suggested for many years and recent reports of the possible importance of active oxygen in chem- ical carcinogenesis are discussed by Nakayama et al. (Carcinogenesis 1983, 4, 765). Free-radical formation in close proximity to tissues causes membrane dam- age owing to lipid peroxidation. The formation of malonic dialdehyde (MDA) is one of the parameters of lipid free-radical damage in cell membranes. Dam- age to nuclear membranes can adversely affect nu- clear pore activity, in addition to causing damage to DNA. Free radicals may also produce changes in membrane-bound enzymes that can adversely affect cell division and dedifferentiation.
A recent paper (Gulumian et al. Chemico-Biol. Interactions 1983, 44, 111) considers the possibility that asbestos fibres produce free radicals, since little is known about lipid peroxidation in pulmonary microsomes exposed to asbestos fibres. Lipid per- oxidation in rat-liver and rat-lung microsomes incu- bated with crocidolite fibres was quantified by col- orimetric determination of MDA formation by complexing with thiobarbituric acid (TBA). The au- thors note that MDA is produced in different phases of this assay. Firstly, it is produced in normal micro-
somes as a result or exposure to air during prepara- tion of the microsomes; secondly, there is metal- catalysed formation of colour during reaction with TBA, a development that can be inhibited by butyl- ated hydroxytoluene; thirdly, MDA can be produced by enzymatic or chemical peroxidation of lipids dur- ing incubation; finally, the free-radical-induced per- oxidation ot" lipids by crocidolite fibres can also produce MDA. The presence o1" crocidolite fibres (5 mg/ml microsomal suspension) in incubations of rat-liver microsomes and of both normal and 3-methylcholanthrene-induced rat-lung microsomes caused a large increase above control incubations in the amount of MDA produced. The increase was statistically significant in all cases. The lack of difference between control results in assays with or without added butylated hydroxytoluene showed that any metal-catalysed reactions were not significant. An estimated 80 95'I,, of the MDA-colour produced after incubations with crocidolite was due to the direct action of crocidolite with tissue lipids, the remainder being due to metal-catalysed artefactual development of colour. The reaction was very rapid, being virtually complete (80~!~,) within 5 rain in rat- lung microsomes.
A direct correlation was found between the amount of asbestos used and the degree of lipid
