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. 2008 Sep 22;6(4):383–396. doi: 10.2203/dose-response.08-013.Pagano

Complex Mixture-Associated Hormesis and Toxicity: The Case of Leather Tanning Industry

Giovanni Pagano 1, Giuseppe Castello 1, Marialuisa Gallo 2, Ilaria Borriello 3, Marco Guida 3
PMCID: PMC2592991  PMID: 19088903

Abstract

A series of studies investigated the toxicities of tannery-derived complex mixtures, i.e. vegetable tannin (VT) from Acacia sp. or phenol-based synthetic tannin (ST), and waste-water from tannin-based vs. chromium-based tanneries. Toxicity was evaluated by multiple bioassays including developmental defects and loss of fertilization rate in sea urchin embryos and sperm (Paracentrotus lividus and Sphaerechinus granularis), and algal growth inhibition (Dunaliella tertiolecta and Selenastrum capricornutum). Both VT and ST water extracts resulted in hormetic effects at concentrations ranging 0.1 to 0.3%, and toxicity at levels ≥1%, both in sea urchin embryo and sperm, and in algal growth bioassays. When comparing tannin-based tannery wastewater (TTW) vs. chromium-based tannery effluent (CTE), a hormesis to toxicity trend was observed for TTW both in terms of developmental and fertilization toxicity in sea urchins, and in algal growth inhibition, with hormetic effects at 0.1 to 0.2% TTW, and toxicity at TTW levels ≥1%. Unlike TTW, CTE showed a monotonic toxicity increase from the lowest tested level (0.1%) and CTE toxicity at higher levels was significantly more severe than TTW-induced toxicity. The results support the view that leather production utilizing tannins might be regarded as a more environmentally friendly procedure than chromium-based tanning process.

Keywords: complex mixtures, tannins, tanneries, sea urchins, microalgae

INTRODUCTION

Hormesis, as a shift from stimulatory or protective effects to inhibitory or toxic effects (Stebbing 1982), had been known in ancient medicine that stated the two-fold meaning of the Greek word "ϕαρμακον", both referred to as “poison” and as “medicinal remedy” according to dosages. In modern laboratory studies Hugo Schulz (1882) first reported the stimulatory effects of low-level poisons in yeast cultures, and the terms “Arndt-Schulz effect” and “Hueppe’s Rule” were utilized in the subsequent studies for several decades. The term “hormesis” was first proposed by Southam and Ehrlich (1943), who reported that extracts of red cedar heartwood (Thuja plicata) stimulated the growth of wood-decaying fungi at low doses, and were inhibitory at higher doses.

In recent decades, a growing body of evidence has accumulated on hormetic effects of several chemical and physical agents tested for a number of biological endpoints in an extended set of cellular systems and organisms (reviewed by Calabrese and Baldwin 2002; Calabrese 2008). However, most reports have focused on individual agents, or on limited sets of chemical analogues, whereas only a few studies have been devoted to hormesis-related effects of complex or model mixtures (Pagano et al. 1986; Kaur et al. 2000; Lehmann et al. 2000; Pautou et al. 2000; Backhaus et al. 2004; Koshy et al. 2008).

Nevertheless, complex mixtures represent the prevailing form of environmentally-occurring contaminants as, e.g., wastewaters, combustion exhausts, or industrial sludge. Thus, investigating complex mixture-associated contamination and toxicity may provide direct information on the impact of anthropogenic pollution sources in environmental and human health (Chapman 2002). In previous studies, we had reported on toxicities of several complex mixtures, as environmentally-occurring and spiked marine and freshwater sediments (Pagano et al. 1993; 2001a; Guillou et al. 2000), industrial wastewater and contaminated soil (Trieff et al. 1995; Pagano et al. 1996; 2002a,b), and a pesticide formulation (Pagano et al. 2001b).

The present review reports on a series of recent studies (2002–2004) of the environmental impact of leather tanning industry with a major focus on tanning agents (vegetable and synthetic tannins), and on tannery wastewaters (De Nicola et al. 2004;2007a,b; Meriç et al. 2005; Oral et al. 2007). Among various results, we found consistent results pointing to a shift from hormetic to toxic effects of both vegetable and synthetic tannins, and of tannin-based tannery wastewater.

LEATHER TANNING WASTEWATER AND SLUDGE

Leather tanning industry is a major subject of concern both in human and environmental health, and the efficiency in abating toxic components from tannery effluents represents a major goal in environmental engineering (Fay and Mumtaz 1996; Tünay et al. 1999; van Groenestijn et al. 2002). We carried out an investigation focussed on tannery wastewater and process sludge, by evaluating the comparative toxicity of several steps in wastewater treatment of chromium-based tanneries (Meriç et al. 2005; Oral et al. 2007) and, subsequently, by comparing toxicity of wastewater from a chromium-based vs. a vegetable tannin-based tannery (De Nicola et al. 2007a). A set of bioassays were utilized in monitoring different endpoints, which included the following: a) sea urchins (Paracentrotus lividus and Sphaerechinus granularis) embryo and sperm bioassays; b) Daphnia magna immobilization, and c) algal growth bioassays (Dunaliella tertiolecta and Selenastrum capricornutum) (Pagano et al. 1986; ASTM 1986; US EPA 1988; 1993). Moreover, some selected agents utilized in leather tanning, including vegetable tannin (VT) from Mimosa sp. and phenol-based synthetic tannin (ST) were evaluated for their concentration-related toxicity trends (De Nicola et al. 2004;2007b).

The present review reports on the hormesis-associated outcomes from this series of studies and is focused on the effects of VT, ST and of tannery wastewater, namely tannin-based tannery wastewater (TTW) and chromium-based tannery wastewater (CTW).

VEGETABLE TANNIN WATER EXTRACT (VTWE)

Sea urchin embryos (P. lividus or S. granularis) were reared in VTWE at concentrations equivalent to Mimosa tannin (dry weight) suspensions ranging from 0.1 mg/L to 30 mg (dry weight)/L, thereafter noted as mg/L. As shown in Figure 1, the observed concentration-related trends of viable larvae displayed a shift from hormesis at low VTWE levels (0.1 mg/L) to developmental toxicity with increasing VTWE levels beyond 1 mg/L up to 30 mg/L. The statistical significance of these data changed dramatically by analyzing the results from the lots with “low-quality” (<70% viable larvae) controls vs. “high-quality” (>70% viable larvae) controls. The hormetic effect at 0.1 mg/L VTWE was highly significant by considering the results from lots with “low-quality” controls (p = 0.009), as shown in Figure 1a. On the other hand, a hormetic trend could be observed, yet was statistically significant in cultures with >70% viable control larvae (Figure 1b), where only developmental toxicity was significant at VTWE levels ranging 3 to 30 mg/L. Positive controls (CdSO4 2.5 × 10–4 M) invariably resulted in 100% developmental arrest or early embryonic mortality, both in “low quality” and in “high quality” cultures, suggesting that the two groups of larval cultures did not differ as to sensitivity to Cd-associated toxicity.

FIGURE 1.

FIGURE 1

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Percent S. granularis viable (Normal+Retarded) plutei following VTWE exposure. Concentrations are expressed as mg VT (dry weight)/L, abbreviated as mg/L. a) Cultures with < 70% normal controls (9 replicates); b) Cultures with ≥ 70% normal controls (5 replicates). Asterisks throughout figures refer to statistical comparisons of experimentals with control batches (Dunnett’s test): *: p <0.05; **: p <0.001; ***: p <0.0001. From De Nicola et al. 2004, with permission.

Fertilization rate (FR = % fertilized eggs) following exposure of S. granularis or P. lividus sperm to VTWE, again, displayed a shift from hormesis to inhibition. As shown in Figure 2, sperm FR was increased by VTWE levels ranging from 0.1 mg/L to 0.3 mg/L, and was then inhibited by increasing VTWE concentrations (1 to 30 mg/L), in the same concentration range both for S. granularis and for P. lividus sperm.

FIGURE 2.

FIGURE 2

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Fertilization rate (% fertilized eggs) of VTWE-exposed S. granularis and P.lividus sperm. From De Nicola et al. 2004, with permission.

The offspring from VTWE-exposed P. lividus sperm resulted in the same non-linear dose-related trend, with a significant increase in viable larvae vs. controls in the offspring of sperm exposed to VTWE levels ranging 0.1 to 1 mg/L, and a concentration-related decrease of viable offspring following sperm exposure to VTWE levels ranging 3 to 30 mg/L (data not shown). Again, the significance of hormetic effects in the offspring of VTWE-exposed sperm was affected according to the 70% cut-off in control quality as reported for VTWE-exposed embryos.

Mitotic activity was affected in S. granularis embryos reared in VT suspensions, with a non-significant increase of the mean number of mitoses per embryo in embryos exposed to 1 mg/L VT, as shown in Figure 3. By increasing VT levels, up to 1 g/L, a significant decline in mitotic activity was observed.

FIGURE 3.

FIGURE 3

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Mitotic activity (Mean number of mitoses per embryo) in S. granularis cleaving embryos (5 hr post-fertilization) exposed to VTWE. From De Nicola et al. 2004, with permission.

In D. magna, a significant concentration-related toxicity was observed at VTWE levels ranging from 200 to 300 mg/L, up to 100% immobilized larvae (data not shown).

Algal bioassays showed a biphasic concentration-related trend for VTWE levels ranging 0.3 to 30 mg/L (Figure 4). Maximum algal growth was observed in D. tertiolecta exposed to 0.3 mg/L VTWE, whereas S. capricornutum responded with maximum growth to 3 mg/L VTWE. A concentration-related growth inhibition was observed in both algal species exposed to VTWE levels ranging 3 to 30 mg/L.

FIGURE 4.

FIGURE 4

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VTWE-modulated cell growth in D. tertiolecta. From De Nicola et al. 2004, with permission.

VEGETABLE VS. SYNTHETIC TANNIN

Sea urchin embryos were reared in VT or ST water extracts (VTWE and STWE) at concentrations ranging from 0.1 mg/L to 10 mg/L. As shown in Figure 5, the concentration-related trends for the frequencies of viable larvae displayed a shift in P. lividus from hormesis at low levels (0.1 mg/L) of VTWE or STWE to developmental toxicity with increasing their levels beyond 1 mg/L up to 10 mg/L. The same trend was observed in S. granularis larvae (data not shown).

FIGURE 5.

FIGURE 5

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Percent P. lividus viable plutei following VTWE and STWE exposure. a) Cultures with <70% normal controls (6 replicates); b) Cultures with ≥ 70% normal controls (16 replicates). From De Nicola et al. 2007b, with permission.

Fertilization rate following exposure of P. lividus sperm to VTWE and STWE was increased by VTWE and STWE at levels ranging from 0.1 mg/L to 0.3 mg/L, and was then inhibited by increasing both VTWE and STWE concentrations (1 to 10 mg/L). The hormetic effect exerted by both VTWE and STWE on P. lividus sperm was highly significant (p <0.0002) when sub-optimal control (FR < 70%) was used (Figure 6a), whereas FR plateaued up to 0.3 mg/L VTWE or STWE, then showed dose-related inhibition at levels ranging 1 to 10 mg/L. On the other hand, sperm lots characterized by higher fertilization rate in controls (FR ≥ 70%) failed to display a significant FR increase at low tannin levels, only exhibiting the concentration-related FR decline at higher tannin levels (Figure 6b). The offspring from VTWE and STWE-exposed P. lividus sperm resulted in the same non-linear dose-related trend (data not shown).

FIGURE 6.

FIGURE 6

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Fertilization rate of VTWE and STWE-exposed P.lividus sperm. a) Cultures with FR < 70% (6 replicates); b) Cultures with FR ≥70% (4 replicates). From De Nicola et al. 2007b, with permission.

TANNIN-BASED VS. CHROMIUM-BASED TANNERY WASTEWATER (TTW AND CTE)

When developing P. lividus embryos were reared in TTW or CTW diluted from 0.1 to 2%, the effects were less severe in TTW-exposed vs. CTW-exposed larvae (p = 0.00002), in that 1% CTW caused 100% developmental arrest (P2), and acute effects were induced by 2% CTW (100% early embryonic mortality), unlike TTW that failed to induce embryonic mortality at the highest (2%) concentration that induced P2 and malformations (P1), as shown in Figure 7. Moreover, CTW-associated toxicity showed a monotonic trend, whereas low-level TTW (0.1%) resulted in lower frequencies of developmental defects than in control cultures (Figure 7).

FIGURE 7.

FIGURE 7

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Percent developmental defects and mortality in P. lividus larvae reared in TTW or CTW for 72 h. Six-replicate experiment. P1: % malformed plutei; P2: % embryos arrested before pluteus stage (blastulae, gastrulae); D: % dead embryos (e.g., pre-hatching arrest). From De Nicola et al. 2007a, with permission.

By exposing P. lividus sperm to TTW, fertilization rate was significantly increased by 0.1% and 0.2% TTW, and then underwent a concentration-related inhibition, however with a FR = 6% at the highest (2%) TTW concentration. Unlike TTW, CTW resulted in a monotonic decrease in fertilization rate, which was significant even at the lowest CTW levels (0.1 to 0.2%), and zeroed at 2% CTW (Figure 8). The offspring of TTW-exposed sperm showed a significant decrease in developmental defects vs. controls following sperm exposure to low-level TTW (0.1%), whereas sperm exposure to 2% TTW resulted in a significant increase in larval malformations. Related to its higher spermiotoxicity, CTW failed to provide any offspring following sperm exposure to 2% CTW. At lower CTW levels, no increase in developmental defects was observed in the offspring (data not shown).

FIGURE 8.

FIGURE 8

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Fertilization rate P. lividus sperm exposed to TTW or CTW. Six-replicate experiment. From De Nicola et al. 2007a, with permission.

In D. magna immobilization tests, TTW resulted in concentration-related toxicity at levels ranging from 6.4 to 12.5%, up to 100% immobililization. Again, CTW exerted a higher toxicity to D. magna, which showed a significant increase in daphnid immobilization reared in 3.2% CTW and resulted in 100% immobililization by 6.4% CTW (data not shown). However, no hormetic effects were detected in D. magna immobilization bioassays. This finding is consistent with the established outcome in D. magna control cultures, exhibiting 100% mobility (or zero immobilization) hence preventing from observing any hormetic effect. Other approaches with daphnid bioassays, e.g. measuring litter size in Ceriodaphnia dubia, are underway.

In algal growth bioassays, exposure to TTW resulted in a non-monotonic concentration-related trend in D. tertiolecta growth, with a significant increase by 0.1% TTW, whereas a slight growth inhibition was only exerted by 2% TTW, as shown in Figure 9. Unlike for TTW, D. tertiolecta showed a concentration-related growth inhibition when exposed to CTW, with total growth inhibition induced by 0.9% CTW (Figure 9).

FIGURE 9.

FIGURE 9

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TTW- and CTW-modulated growth inhibition in D. tertiolecta. Four-replicate experiment. From De Nicola et al. 2007a, with permission.

DISCUSSION

Hormetic effects have been reported in previous studies of tannin-associated toxicity starting from the pioneering study by Southam and Ehrlich (1943) and in recent reports (Haslam 1988; Chen and Chung 2000; Kaur et al. 2000; Lehmann et al. 2000; Pautou et al. 2000; Rajalakshmi et al. 2001; Sasaki et al. 1990; Wang et al. 2001). Tannins, due to their polyphenolic structure, may be viewed as a relevant case for hormesis-inducing agent as expected from the recognized shifts from tannin-associated chelation to biomolecule denaturation (Andrade et al. 2005; Lestienne et al. 2005). One may speculate that low-level tannins (or tannin-related compounds) may be involved in chelating a number of contaminants, e.g. metal ions as iron or copper. Scavenging radical-catalyzing metals (Strličet al. 2002), in turn, may result in protection of biomolecule structures from oxidative stress and in better performance of several cellular events. On the other hand, increasing tannin levels induce concentration-related damage to biomolecules, hence causing concentration-related loss of cellular functions.

Consistent with the findings on tannin-related hormesis, tannery wastewaters showed a specific hormetic effect of tannin-based, but not of chromium-based tannery effluent. Altogether, the available evidence from the environmental impact of CTW points to unsolved environmental concern about chromium-based leather tanning process (Chattopadhyay et al. 1999; Klinkow et al. 1998; Vijayaraghavan and Murthy 1997). On the other hand, the present data on TTW, with a concentration-related shift from hormesis to moderate toxicity suggest that tannin-based tanning process might be considered as a more environmentally friendly procedure in leather production.

Two final comments may arise from the present series of studies regarding the detection of hormetic effects. First, we did find consistent hormetic trends throughout tannin-containing or tannin-related mixtures, including Mimosa wood, phenol-based synthetic tannin, and tannin-operated tannery wastewater. However, chromium-based tannery waste-water did not display any hormetic trend; also lacking any hormetic effects were a number of other chemicals tested throughout our previous studies. Thus, our overall results, unconfined to the present study, do not allow us to view hormesis as a generalized phenomenon.

Another relevant consequence of the present study points to the criteria in defining control quality. In testing sea urchin larval development, and in sea urchin sperm bioassays adjusting control values (either larval quality or fertilization rate) at suboptimal values enabled us to observe both toxic and hormetic effects (Pagano et al., 1986; De Nicola et al. 2004;2007a,b). Such effects would be overlooked by applying the traditional criteria assuming that only cultures with high-quality controls should be taken into account. Establishing new definitions for control quality in conducting bioassays is mandatory for detecting both hormetic and or toxic outcomes. As long as control values were determined for measurable parameters (e.g., growth rate or enzyme activity), hormetic or inhibitory effects could be referred to discrete control values; then increased or decreased values in test schedules would be obviously detected. On the other hand, the occurrence of morphologic abnormalities, or the success of a given event (e.g., fertilization) have been traditionally assumed as displaying extreme percent values in controls, as either zero or hundred (see, e.g., Ghirardini et al., 2001). The current axiom in the assignment of control values, however, may both conceal a loss of bioassay sensitivity, or may make any measurement of hormetic effects impossible or not significant. Thus, one may anticipate the need for a novel definition of control values at percent frequencies that both allow for the measurement of minor inhibitory effects and make the observation of hormetic effects feasible.

Acknowledgments

This study was supported by the NATO Science Programme, grant SA(EST.CLG.978615). The authors declare they have no competing financial interests.

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