Combined Actions and Interactions of Chemicals in Mixtures

More documents

Recommendations

Info

stannous chloride and cadmium chloride resulting in a lower ASAT activity than expected on the basis of additivity. As expected, the carboxyhaemoglobin formation was mainly due to dichloromethane and no interactions with other compounds were observed. Aspirin, DEHP, and surprisingly stannous chloride increased the incidence of hepatocellular hypertrophy and there were no significant cases of interaction in the liver. The factorial analysis revealed a slightly increased incidence of epithelial hyperplasia in the nasal cavity in rats exposed to dichloromethane in the absence of formaldehyde. However, in the presence of formaldehyde most of the rats showed epithelial hyperplasia independent of the presence or absence of dichloromethane. In the main study the only treatment related effects observed in the NOAEL group were decreased alkaline phosphatase activity and triglyceride concentration and slight and infrequent hypertrophy of liver cells and epithelial cells of the nasal cavity. Liver changes had previously been observed after administration of DEHP, aspirin or spermine at higher doses, and changes in the nasal cavity is characteristic for the effect of formaldehyde. Relative kidney weights were increased in rats of the NOAEL and one-third the NOAEL groups. The satellite part of the study revealed that BHA, aspirin, or stannous chloride might increase the kidney weight. The effect on kidney weight at the LOAEL could well be explained by summation of the effects of BHA, aspirin and stannous chloride and a similar joint (additive) action of these compounds might also explain the in crease in kidney weight at the NOAEL. It was concluded that simultaneous exposure to these nine chemicals did not constitute an evidently increased hazard compared to exposure to each of the chemicals separately, provided the exposure level of each chemical in the mixture was at most similar to or lower than its own NOAEL (Groten et al. 1997). In comparison with the adverse effects produced by the individual compounds, both more severe and less severe effects were observed at the LOAEL of the combined compounds, indicating interactions of effects at this exposure level. Several of the effects (growth retardation, reduced food intake, and liver damage) were more severe than seen with the individual compounds. 5.2.1 Other studies Ito et al. (1995) examined the combined dietary administration to rats of 19 organophosphorus compounds and one organochlorine pesticide, all permitted for use in Japan, each at its acceptable daily intake (ADI) level. The dietary exposure at this level did not enhance the development of rat liver preneoplastic lesions initiated by diethylnitrosamine. However, a mixture administered at 100 times the ADI levels of the pesticides significantly increased the number and area of lesions. The authors concluded that the study provided direct support for the present use of the safety factor approach in the quantitative hazard evaluation of pesticides. Swiss albino male rats were treated orally by gavage with 100- and 1000-fold the ADI of endosulfan, dimethoate and carbaryl (Akay et al., 1999). The authors had previously reported that endosulfan, dimethoate and carbaryl, either alone or in mixture at 1- and 10-fold the ADIs, did not cause significant effects on immunological and haematological parameters of rats. No effects were reported on immunoglobulin concentrations or blood parameters at the 100-fold ADI level as well as after treatment with the individual pesticides. It was concluded that the mixtures acted like the single compounds and that no synergistic or antagonistic effects were observed. However, the authors ignored elevations in the red blood 64
cell and monocyte counts in the rats receiving a mixture of endosulfan and dimethoate. They also ignored effect on the red blood cell counts in rats receiving a mixture of dimethoate and carbaryl. At 1000-fold the ADIs indication of immune suppression was reported to depend on the presence of endosulfan. The authors suggest that carbaryl had a slight antagonistic effect on endosulfan and dimethoate at high doses. Wade et al. (2002) studied the subchronic effects (systemic, immune, and reproductive effects) of exposure to a complex mixture of persistent contaminants in sexually mature male rats. Each chemical was included in the mixture at the “minimum risk level” (MRL), the reference dose (RfD) or tolerable daily intake (TDI) as determined by ATSDR or US EPA. For 2,3,7,8-tetrachlorodibenzo-pdioxin (TCDD) the NOAEL (1 ng/kg bw/day) used to calculate the TDI in Canada in 1993 was used. The rats were exposed to the mixture at 1, 10, 100, and 1000 times the estimated safe levels daily for 70 days (see table 5.2.3). Table 5.2.3. Composition of contaminant mixture administered to male rats Contaminant 1 x MRL/RfD/TDI (xg/kg bw/d) 10x MRL/RfD/TDI (xg/kg bw/d) 100 x MRL/RfD/TDI (xg/kg bw/d) 1000 x MRL/RfD/TDI (xg/kg bw/d) Aldrin 30 ng 0.3 µg 3 µg 30 µg p,p’-DDT 30 ng 0.3 µg 3 µg 30 µg p,p’-DDE 570 ng 5.7 µg 57 µg 570 µg Dieldrin 50 ng 0.5 µg 5 µg 50 µg Endosulfan 50 ng 0.5 µg 5 µg 50 µg Heptachlor 0.5 µg 5 µg 50 µg 500 µg Hexachlorbenzene 0.3 µg 3 µg 30 µg 300 µg Hexachlorocyclohexane 0.3 µg 3 µg 30 µg 300 µg Mirex 0.8 µg 8 µg 80 µg 800 µg Methoxychlor 2 µg 20 µg 200 µg 2000 µg 1,2,3-Trichlorobenzene 0.77 µg 7.7 µg 77 µg 770 µg 1,2,4-Trichlorobenzene 2.3 µg 23 µg 230 µg 2300 µg 1,2,3,4- 0.2 µg 2 µg 20 µg 200 µg Tetrachlorobenzene Pentachlorobenzene 0.5 µg 5 µg 50 µg 500 µg TCDD 1 ng 10 ng 0.1 µg 1 µg PCB (Aroclor 1254) 1 µg 10 µg 100 µg 1000 µg Cadmium chloride 0.7 µg 7 µg 70 µg 700 µg Lead chloride 0.1 ng 1 ng 10 ng 0.1 µg Evidence of hepatotoxicity was seen as a significant enlargement of the liver in the 1000x group, reduced serum LDH activity (100x), and increased serum cholesterol and protein levels (both 1000x). Hepatic EROD activities (a marker of cytochrome P450 activity) were elevated in animals exposed to 10x and above. The mixture caused decreased proliferation of spleenic T cells at the highest dose and had a biphasic effect on natural killer cell lytic activity with an initial increase in activity at 1x followed by a decrease to below control levels in response to 1000x. No treatment-related effects were seen on bone marrow micronuclei, daily sperm production, serum LH, FSH, or prolactin levels or weights of most organs of the reproductive tract. The weights of the whole epididymis and the caput epididymis were significantly decreased at 10x and higher doses. However, no effect was seen on cauda epididymal weight. The sperm content of the cauda epididymis was increased at the 1x level but not significantly different from control at higher levels. A slight, but significant, increase in the relative numbers of spermatids was 65
Page 1 and 2:
Combined Actions and Interactions o
Page 3 and 4:
Contents CONTENTS 3 PREFACE 6 SAMME
Page 5 and 6:
7.2.4 Test systems 85 7.2.5 In vitr
Page 7 and 8:
Sammenfatning og konklusioner Indle
Page 9 and 10:
er ingen viden om, hvorledes den ko
Page 11 and 12:
estemt biologisk respons (ED10, ED2
Page 13 and 14: vivo. The COMET-assay in vivo and g
Page 15 and 16: and antagonistic effects may be see
Page 17 and 18: 1 Introduction Prepared by John Chr
Page 19 and 20: Table 1.3.1: Classification of comb
Page 21 and 22: Physicochemical interactions will t
Page 23 and 24: US EPA (1986) applied the concept o
Page 25 and 26: 2.4 Test strategies to assess combi
Page 27 and 28: Figure 2.4.3.1. Isobologram of two
Page 29 and 30: CI = d1 /D1 = 1 In this case the is
Page 31 and 32: 2.5 Toxicological test methods When
Page 33 and 34: 3 General concepts in the risk asse
Page 35 and 36: NOAEL, this indicates that the subs
Page 37 and 38: of uncertainty i.e. differences in
Page 39 and 40: describe toxicities that appears to
Page 41 and 42: should be estimated for all endpoin
Page 43 and 44: 1,2,3,6,7,8-HxCDF 0.1 1,2,3,7,8,9-H
Page 45 and 46: shows the pronounced influence of t
Page 47 and 48: Table 4.3.1 Estimates of carcinogen
Page 49 and 50: Figure 4.4.1.1. Scheme for safety e
Page 51 and 52: obvious ranking of individual const
Page 53 and 54: 4.5 Approach for assessment of join
Page 55 and 56: 4.6 Approaches currently used by re
Page 57 and 58: no internationally accepted procedu
Page 59: Figure 4.6.3.1 Flow chart of the ri
Page 62 and 63: octyltin dichloride). A number of a
Page 66 and 67: seen in the animals from the 1000x
Page 68 and 69: c TCTFP = 1,1,2-trichloro-3,3,3-tri
Page 70 and 71: 6 Interactions in toxicokinetics Pr
Page 72 and 73: once more exposed and the kinetics
Page 74 and 75: Dermis The dermis consists of a sup
Page 76 and 77: 7.1.3 Ocular irritancy 7.1.3.1 Comp
Page 78 and 79: Another in vitro test for ocular ir
Page 80 and 81: lipid peroxidation was observed, wh
Page 82 and 83: mixture. These interactions may dev
Page 84 and 85: 0.6% of live births in humans. In s
Page 86 and 87: DNA, and that the cell was capable
Page 88 and 89: (Sorsa et al. 1994, Myslak & Kosmid
Page 90 and 91: Four inhibitors of DNA topoisomeras
Page 92 and 93: cyclophosphamide-metabolising enzym
Page 94 and 95: Nickel compounds are carcinogenic t
Page 96 and 97: 7.2.8 Conclusion As shown in this r
Page 98 and 99: Since no compounds are known to cau
Page 100 and 101: In a more mechanistic sense, promot
Page 102 and 103: Several inhibitors of tumour promot
Page 104 and 105: Table 7.4.1.1 Overview of in vivo t
Page 106 and 107: analysis was used to predict the hi
Page 108 and 109: interaction of TCDD and retinoic ac
Page 110 and 111: and now includes compounds as diver
Page 112 and 113: Furthermore, the estrogenic effects
Page 114 and 115:
Dose of A (arbitrary units) 10 8 6
Page 116 and 117:
chance or experimental error. One w
Page 118 and 119:
7.6.2.3 Receptors A receptor is a b
Page 120 and 121:
7.6.5.2 Kindling Kindling is the ph
Page 122 and 123:
Science Institute (RSI) have conven
Page 124 and 125:
eaction with sulfhydryl groups). Th
Page 126 and 127:
7.7.1.3 Mechanisms of immunotoxicit
Page 128 and 129:
tested separately. This is a phenom
Page 130 and 131:
In practical life an allergen may b
Page 132 and 133:
8.3 Conference proceedings Proceedi
Page 134 and 135:
with combinations of environmental
Page 136 and 137:
Boyd MR, Statham CM and Longo NS (1
Page 138 and 139:
De Wall EJ, Schuurman HJ and Van Lo
Page 140 and 141:
theoretical considerations and a su
Page 142 and 143:
Groten JP, Sinkeldam EJ, Muys T, Lu
Page 144 and 145:
Howes D, Guy R, Hadgraft J, Heyling
Page 146 and 147:
cytochrome P450 1A2 expressed in Am
Page 148 and 149:
Lison D, Carbonnelle P, Mollo L, La
Page 150 and 151:
Narotsky MG, Weller EA, Chinchilli
Page 152 and 153:
Ramsey JC and Andersen ME (1984). A
Page 154 and 155:
Silva E, Rajapakse N and Kortenkamp
Page 156 and 157:
Leeuwen FXR, Liem AKD, Nolt C, Pete
Page 158:
Wlodarczyk B, Biernacki B, Minta M,
show all

Combined Actions and Interactions of Chemicals in Mixtures

You also want an ePaper? Increase the reach of your titles

Delete template?

Save as template?