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

COMPLEX MIXTURE-ASSOCIATED HORMESIS AND TOXICITY: THE CASE OFLEATHER TANNING INDUSTRY

Giovanni Pagano, Giuseppe Castello � Cancer Research Center, CROM, I-83013Mercogliano (AV), Italy

Marialuisa Gallo � Campania Regional Environmental Protection Agency(ARPAC), I-80143 Naples, Italy

Ilaria Borriello, Marco Guida � Federico II Naples University, Department ofBiological Sciences, I-80134 Naples, Italy

� 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 multiplebioassays including developmental defects and loss of fertilization rate in sea urchinembryos and sperm (Paracentrotus lividus and Sphaerechinus granularis), and algal growthinhibition (Dunaliella tertiolecta and Selenastrum capricornutum). Both VT and ST waterextracts resulted in hormetic effects at concentrations ranging 0.1 to 0.3%, and toxicity atlevels ≥1%, both in sea urchin embryo and sperm, and in algal growth bioassays. Whencomparing tannin-based tannery wastewater (TTW) vs. chromium-based tannery effluent(CTE), a hormesis to toxicity trend was observed for TTW both in terms of developmen-tal and fertilization toxicity in sea urchins, and in algal growth inhibition, with hormeticeffects at 0.1 to 0.2% TTW, and toxicity at TTW levels ≥1%. Unlike TTW, CTE showed amonotonic toxicity increase from the lowest tested level (0.1%) and CTE toxicity at high-er levels was significantly more severe than TTW-induced toxicity. The results support theview that leather production utilizing tannins might be regarded as a more environmen-tally 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 inhibito-ry or toxic effects (Stebbing 1982), had been known in ancient medicinethat stated the two-fold meaning of the Greek word “φαρμακον”, bothreferred to as “poison” and as “medicinal remedy” according to dosages.In modern laboratory studies Hugo Schulz (1882) first reported the stim-ulatory effects of low-level poisons in yeast cultures, and the terms “Arndt-Schulz effect” and “Hueppe’s Rule” were utilized in the subsequent stud-ies for several decades. The term “hormesis” was first proposed bySoutham and Ehrlich (1943), who reported that extracts of red cedar

Dose-Response, 6:383–396, 2008Formerly Nonlinearity in Biology, Toxicology, and MedicineCopyright © 2008 University of MassachusettsISSN: 1559-3258DOI: 10.2203/dose-response.08-013.Pagano

Address correspondence to Giovanni Pagano, Cancer Research Center, CROM, viaAmmiraglio Bianco, 13, I-83013 Mercogliano (AV), Italy; Tel.: 39-335-7907261; Fax: 39-0825-511146; E-mail: [email protected]

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heartwood (Thuja plicata) stimulated the growth of wood-decaying fungiat low doses, and were inhibitory at higher doses.

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

Nevertheless, complex mixtures represent the prevailing form ofenvironmentally-occurring contaminants as, e.g., wastewaters, combus-tion exhausts, or industrial sludge. Thus, investigating complex mixture-associated contamination and toxicity may provide direct information onthe impact of anthropogenic pollution sources in environmental andhuman health (Chapman 2002). In previous studies, we had reported ontoxicities of several complex mixtures, as environmentally-occurring andspiked marine and freshwater sediments (Pagano et al. 1993; 2001a;Guillou et al. 2000), industrial wastewater and contaminated soil (Trieffet 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 majorfocus on tanning agents (vegetable and synthetic tannins), and on tan-nery wastewaters (De Nicola et al. 2004;2007a,b; Meriç et al. 2005; Oral etal. 2007). Among various results, we found consistent results pointing toa shift from hormetic to toxic effects of both vegetable and synthetic tan-nins, and of tannin-based tannery wastewater.

LEATHER TANNING WASTEWATER AND SLUDGE

Leather tanning industry is a major subject of concern both inhuman and environmental health, and the efficiency in abating toxiccomponents from tannery effluents represents a major goal in environ-mental engineering (Fay and Mumtaz 1996; Tünay et al. 1999; vanGroenestijn et al. 2002). We carried out an investigation focussed on tan-nery wastewater and process sludge, by evaluating the comparative toxic-ity of several steps in wastewater treatment of chromium-based tanneries(Meriç et al. 2005; Oral et al. 2007) and, subsequently, by comparing tox-icity of wastewater from a chromium-based vs. a vegetable tannin-basedtannery (De Nicola et al. 2007a). A set of bioassays were utilized in moni-toring different endpoints, which included the following: a) sea urchins(Paracentrotus lividus and Sphaerechinus granularis) embryo and spermbioassays; b) Daphnia magna immobilization, and c) algal growth bioassays

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(Dunaliella tertiolecta and Selenastrum capricornutum) (Pagano et al. 1986;ASTM 1986; US EPA 1988; 1993). Moreover, some selected agents utilizedin leather tanning, including vegetable tannin (VT) from Mimosa sp. andphenol-based synthetic tannin (ST) were evaluated for their concentra-tion-related toxicity trends (De Nicola et al. 2004;2007b).

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

VEGETABLE TANNIN WATER EXTRACT (VTWE)

Sea urchin embryos (P. lividus or S. granularis) were reared in VTWEat concentrations equivalent to Mimosa tannin (dry weight) suspensionsranging from 0.1 mg/L to 30 mg (dry weight)/L, thereafter noted asmg/L. As shown in Figure 1, the observed concentration-related trendsof viable larvae displayed a shift from hormesis at low VTWE levels (0.1

Complex mixture hormesis and toxicity

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FIGURE 1. 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). Asterisksthroughout figures refer to statistical comparisons of experimentals with control batches (Dunnett’stest): *: p <0.05; **: p ≤0.001; ***: p <0.0001. From De Nicola et al. 2004, with permission.

mg/L) to developmental toxicity with increasing VTWE levels beyond 1mg/L up to 30 mg/L. The statistical significance of these data changeddramatically by analyzing the results from the lots with “low-quality”(<70% viable larvae) controls vs. “high-quality” (>70% viable larvae) con-trols. The hormetic effect at 0.1 mg/L VTWE was highly significant byconsidering the results from lots with “low-quality” controls (p = 0.009),as shown in Figure 1a. On the other hand, a hormetic trend could beobserved, yet was statistically significant in cultures with >70% viable con-trol larvae (Figure 1b), where only developmental toxicity was significantat VTWE levels ranging 3 to 30 mg/L. Positive controls (CdSO4 2.5 × 10–4

M) invariably resulted in 100% developmental arrest or early embryonicmortality, both in “low quality” and in “high quality” cultures, suggestingthat the two groups of larval cultures did not differ as to sensitivity to Cd-associated toxicity.

Fertilization rate (FR = % fertilized eggs) following exposure of S.granularis or P. lividus sperm to VTWE, again, displayed a shift fromhormesis to inhibition. As shown in Figure 2, sperm FR was increased byVTWE levels ranging from 0.1 mg/L to 0.3 mg/L, and was then inhibit-


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FIGURE 2. Fertilization rate (% fertilized eggs) of VTWE-exposed S. granularis and P.lividus sperm.From De Nicola et al. 2004, with permission.

ed by increasing VTWE concentrations (1 to 30 mg/L), in the same con-centration range both for S. granularis and for P. lividus sperm.

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

Mitotic activity was affected in S. granularis embryos reared in VT sus-pensions, with a non-significant increase of the mean number of mitosesper embryo in embryos exposed to 1 mg/L VT, as shown in Figure 3. Byincreasing VT levels, up to 1 g/L, a significant decline in mitotic activitywas observed.

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

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


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FIGURE 3. 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.

VEGETABLE VS. SYNTHETIC TANNIN

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

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


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FIGURE 4. VTWE-modulated cell growth in D. tertiolecta. From De Nicola et al. 2004, with permission.

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

When developing P. lividus embryos were reared in TTW or CTWdiluted 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% devel-opmental arrest (P2), and acute effects were induced by 2% CTW (100%early embryonic mortality), unlike TTW that failed to induce embryonicmortality at the highest (2%) concentration that induced P2 and malfor-mations (P1), as shown in Figure 7. Moreover, CTW-associated toxicityshowed a monotonic trend, whereas low-level TTW (0.1%) resulted inlower frequencies of developmental defects than in control cultures(Figure 7).

By exposing P. lividus sperm to TTW, fertilization rate was significant-ly increased by 0.1% and 0.2% TTW, and then underwent a concentra-


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FIGURE 5. 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). FromDe Nicola et al. 2007b, with permission.

tion-related inhibition, however with a FR = 6% at the highest (2%) TTWconcentration. Unlike TTW, CTW resulted in a monotonic decrease infertilization rate, which was significant even at the lowest CTW levels (0.1to 0.2%), and zeroed at 2% CTW (Figure 8). The offspring of TTW-exposed sperm showed a significant decrease in developmental defectsvs. controls following sperm exposure to low-level TTW (0.1%), whereassperm exposure to 2% TTW resulted in a significant increase in larvalmalformations. Related to its higher spermiotoxicity, CTW failed to pro-vide any offspring following sperm exposure to 2% CTW. At lower CTWlevels, no increase in developmental defects was observed in the offspring(data not shown).

In D. magna immobilization tests, TTW resulted in concentration-related toxicity at levels ranging from 6.4 to 12.5%, up to 100% immo-bililization. Again, CTW exerted a higher toxicity to D. magna, which


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FIGURE 6. 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.

showed a significant increase in daphnid immobilization reared in 3.2%CTW and resulted in 100% immobililization by 6.4% CTW (data notshown). However, no hormetic effects were detected in D. magna immo-bilization bioassays. This finding is consistent with the established out-come in D. magna control cultures, exhibiting 100% mobility (or zeroimmobilization) hence preventing from observing any hormetic effect.Other approaches with daphnid bioassays, e.g. measuring litter size inCeriodaphnia dubia, are underway.

In algal growth bioassays, exposure to TTW resulted in a non-monot-onic concentration-related trend in D. tertiolecta growth, with a significantincrease by 0.1% TTW, whereas a slight growth inhibition was only exert-ed by 2% TTW, as shown in Figure 9. Unlike for TTW, D. tertiolecta showeda concentration-related growth inhibition when exposed to CTW, withtotal growth inhibition induced by 0.9% CTW (Figure 9).

DISCUSSION

Hormetic effects have been reported in previous studies of tannin-associated toxicity starting from the pioneering study by Southam andEhrlich (1943) and in recent reports (Haslam 1988; Chen and Chung


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FIGURE 7. Percent developmental defects and mortality in P. lividus larvae reared in TTW or CTWfor 72 h. Six-replicate experiment. P1: % malformed plutei; P2: % embryos arrested before pluteusstage (blastulae, gastrulae); D: % dead embryos (e.g., pre-hatching arrest). From De Nicola et al.2007a, with permission.

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, dueto their polyphenolic structure, may be viewed as a relevant case forhormesis-inducing agent as expected from the recognized shifts from tan-nin-associated chelation to biomolecule denaturation (Andrade et al.


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FIGURE 8. Fertilization rate P. lividus sperm exposed to TTW or CTW. Six-replicate experiment.From De Nicola et al. 2007a, with permission.

FIGURE 9. TTW- and CTW-modulated growth inhibition in D. tertiolecta. Four-replicate experiment.From De Nicola et al. 2007a, with permission.

2005; Lestienne et al. 2005). One may speculate that low-level tannins (ortannin-related compounds) may be involved in chelating a number ofcontaminants, e.g. metal ions as iron or copper. Scavenging radical-cat-alyzing metals (Strlic et al. 2002), in turn, may result in protection of bio-molecule structures from oxidative stress and in better performance ofseveral cellular events. On the other hand, increasing tannin levelsinduce concentration-related damage to biomolecules, hence causingconcentration-related loss of cellular functions.

Consistent with the findings on tannin-related hormesis, tannerywastewaters showed a specific hormetic effect of tannin-based, but not ofchromium-based tannery effluent. Altogether, the available evidencefrom the environmental impact of CTW points to unsolved environmen-tal concern about chromium-based leather tanning process(Chattopadhyay et al. 1999; Klinkow et al. 1998; Vijayaraghavan andMurthy 1997). On the other hand, the present data on TTW, with a con-centration-related shift from hormesis to moderate toxicity suggest thattannin-based tanning process might be considered as a more environ-mentally friendly procedure in leather production.

Two final comments may arise from the present series of studiesregarding the detection of hormetic effects. First, we did find consistenthormetic trends throughout tannin-containing or tannin-related mix-tures, 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 hormeticeffects were a number of other chemicals tested throughout our previousstudies. Thus, our overall results, unconfined to the present study, do notallow us to view hormesis as a generalized phenomenon.

Another relevant consequence of the present study points to the cri-teria in defining control quality. In testing sea urchin larval development,and in sea urchin sperm bioassays adjusting control values (either larvalquality or fertilization rate) at suboptimal values enabled us to observeboth toxic and hormetic effects (Pagano et al., 1986; De Nicola et al.2004;2007a,b). Such effects would be overlooked by applying the tradi-tional criteria assuming that only cultures with high-quality controlsshould be taken into account. Establishing new definitions for controlquality in conducting bioassays is mandatory for detecting both hormet-ic and or toxic outcomes. As long as control values were determined formeasurable parameters (e.g., growth rate or enzyme activity), hormeticor inhibitory effects could be referred to discrete control values; thenincreased or decreased values in test schedules would be obviously detect-ed. On the other hand, the occurrence of morphologic abnormalities, orthe success of a given event (e.g., fertilization) have been traditionallyassumed as displaying extreme percent values in controls, as either zeroor hundred (see, e.g., Ghirardini et al., 2001). The current axiom in the


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assignment of control values, however, may both conceal a loss of bioas-say sensitivity, or may make any measurement of hormetic effects impos-sible or not significant. Thus, one may anticipate the need for a novel def-inition of control values at percent frequencies that both allow for themeasurement of minor inhibitory effects and make the observation ofhormetic effects feasible.

ACKNOWLEDGMENTS

This study was supported by the NATO Science Programme, grantSA(EST.CLG.978615). The authors declare they have no competingfinancial interests.

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

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